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Kaimen Rigor review

Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial.

Tesser JRP, Crowley AR, Box EJ, June JP, Wickersham PB, Valenzuela GJ, Gaylis NB, Lam GKW, Pacheco LA, Ridley DJ, Pinto-Patarroyo GP, Novack SN, Churchill MA, Kohler M, Lee EC, Pando JA, Parris GR, Peterson JR, Shah T, Singhal AK, Vuong V, Levine YA, Evangelista ML, Derosier AA, Curtis JR, Richardson RM, Chernoff D

DOI: 10.1038/s41591-025-04114-7
Record issued: 2026-08-15
Engine: 7.39.0
Exported: 2026-09-20

Prepared by Alpha1. This document is confidential: it is intended for the recipient it was shared with and must not be redistributed. The live record at alpha1science.com/verify/a6345c28-3113-438b-addf-1086bc847d76 is authoritative.

Kaimen Rigor review

Kaimen Rigor reviewed

2 / 5

Weak — serious problems found

Interventional Study

Critical

High-priority

How this rating was calculated

Started at 5★ — deductions

IntegrityIntegrity concern ×4−2★
ClaimsEfficacy rests on an unvalidated surrogate endpoint−0.5★
ClaimsTreatment effect not shown to be clinically meaningful−0.5★

Model-reported confidence: highReviewer agreement: highEngine: 7.39.0Source: full text

Not verified in this report

The numeric-impossibility checks (GRIM/GRIMMER/DEBIT/SPRITE) did not run: 24 reported means were read, and their group size is not stated where the values are printed (this source has no machine-readable table structure). These checks need the count the mean was averaged over, so none was performed.

Biggest issues

01Efficacy rests on an unvalidated surrogate endpoint
highOverreachreviewer-assessedFull detail
The primary efficacy claim is based on ACR20 response, which is a composite clinical measure of disease activity, not a hard clinical outcome. Although ACR20 is a validated clinical endpoint in RA trials, the paper does not demonstrate target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor cite validated evidence linking ACR20 to long-term clinical outcomes such as mortality or disability. The surrogate is the ACR20 response, and the missing element is the explicit validation of this surrogate as a predictor of clinical benefit.
“The primary end point was a difference in proportion of patients in the ITT population receiving stimulation versus sham who achieved an ACR20 response at the 3-month visit from baseline (day of consent).”
Find in source
02Treatment effect not shown to be clinically meaningful
highOverreachreviewer-assessedFull detail
The primary effect size is an 11.8% absolute difference in ACR20 response rates (35.2% vs 24.2%), which is statistically significant but small. The paper itself notes that this effect size was smaller than the projected 25% and smaller than typically reported in drug trials. No minimal clinically important difference (MCID) for ACR20 is provided, and the clinical meaningfulness of this difference is not explicitly anchored. The effect size is presented as positive but lacks a clear anchor to clinical meaningfulness.
“the effect size of 11.8% was smaller than the projected effect size of 25% and smaller than that typically reported in drug trials at 3 months”
Find in source

Findings by category

101ArithmeticNumerical inconsistencies 202OverreachOverstated conclusions 03AuthenticityNone found 04DisclosureNone found 05AvailabilityNone found 06Copyedit6 minor suggestions

This Kaimen Rigor review uses Kaimen Rigor reviewers trained on a curated corpus of high-fidelity and retracted papers, with expert supervision and curation. It can still make mistakes; verify each finding against the source before relying on it.

This is a well-conducted pivotal randomized sham-controlled trial with rigorous design, clear reporting of ethics, statistics, and data availability. Minor copyedit issues (typos, formatting) and a small internal inconsistency in the safety denominator do not undermine the overall integrity.

Both reviewers classified the study as interventional and agreed on all dimensions. The statistics verification covered only a subset of tests (those with test statistics/df or effect estimates with CIs); threshold-only p-values and resampling-based tests were not machine-verified. The integrity check flagged a minor denominator discrepancy in the safety event rate (242 vs 243) that warrants clarification.

Numerical inconsistencies

1 finding · worst low

Values that contradict each other or are impossible for the stated sample: recomputed p-values and test statistics, GRIM/GRIMMER checks on summary numbers, percentages against their own counts, totals against their parts, and estimates against their own confidence intervals.

Internal contradictions in the reported numbersAssessed

Recomputed 5 tests: 5 consistent, 0 inconsistent; 5 via agent-written checks.

Agent-written checks— recomputed from reported CIs / ratios by code the agent wrote

CONSISTENTreported p = .021 · recomputed p = .040Reviewer 1
Primary endpoint ACR20 response difference between arms at 3 months.
“The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P = 0.0209, 95% confidence interval (CI) = 0.6, 23.1).”
Find in source
Taken as given: The reported difference is 11.8% (0.118).; The 95% CI is (0.6%, 23.1%) = (0.006, 0.231).; The p-value is two-sided from the CI.
Method: Recomputed two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.118, 0.006, 0.231, 0)
CONSISTENTreported p = .005 · recomputed p = .002Reviewers 1, 2
EULAR good/moderate response difference at 3 months.
“EULAR good/moderate response was achieved by 60.7% of arm 1 (stimulation) and by 41.7% of arm 2 (sham) (multiplicity-adjusted P = 0.0048, 95% CI = 7.3, 31.7).”
Find in source
Taken as given: The reported difference is 60.7% - 41.7% = 19.0% (0.19).; The 95% CI is (7.3%, 31.7%) = (0.073, 0.317).; The p-value is two-sided from the CI.
Method: Recomputed two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.19, 0.073, 0.317, 0)
UNCOMPUTABLEreported p = .015 · recomputed p = .040Reviewers 1, 2
DAS28-CRP LDA/remission difference at 3 months.
“DAS28-CRP LDA/remission (% rate ± s.e.m.—arm 1 = 26.1% ± 4, arm 2 = 15.4% ± 3; P = 0.0154, 95% CI = 1.2, 21.6).”
Find in source
Taken as given: The reported difference is 26.1% - 15.4% = 10.7% (0.107).; The 95% CI is (1.2%, 21.6%) = (0.012, 0.216).; The p-value is two-sided from the CI.
Method: Recomputed two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.107, 0.012, 0.216, 0)
CONSISTENTreported p = .021 · recomputed p = .040Reviewer 2
Primary endpoint ACR20 response difference between stimulation and sham at 3 months.
“The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P = 0.0209, 95% confidence interval (CI) = 0.6, 23.1).”
Find in source
Taken as given: The reported difference is 11.8% (0.118) and the 95% CI is 0.6% to 23.1% (0.006 to 0.231).; The p-value is derived from the confidence interval for a difference in proportions.; The CI is two-sided at 95%.
Method: Recomputed the two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.118, 0.006, 0.231, 0)
CONSISTENTreported p = .053 · recomputed p = .041Reviewer 2
Secondary endpoint DAS28-CRP MCID difference at 3 months.
“DAS28-CRP MCID was achieved by 45.1% of arm 1 and by 32.5% of arm 2 (multiplicity-adjusted P = 0.0528, 95% CI = 1.1, 25.3).”
Find in source
Taken as given: The reported difference is 12.6% (0.126) and the 95% CI is 1.1% to 25.3% (0.011 to 0.253).; The p-value is derived from the confidence interval for a difference in proportions.; The CI is two-sided at 95%.
Method: Recomputed the two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.126, 0.011, 0.253, 0)
CONSISTENTreported p = .080 · recomputed p = .144Reviewer 2
Secondary endpoint HAQ-DI MCID difference at 3 months.
“HAQ-DI MCID was achieved by 45.9% of arm 1 and by 36.7% of arm 2 (multiplicity-adjusted P = 0.0797, 95% CI = −3.3, 21.4).”
Find in source
Taken as given: The reported difference is 9.2% (0.092) and the 95% CI is -3.3% to 21.4% (-0.033 to 0.214).; The p-value is derived from the confidence interval for a difference in proportions.; The CI is two-sided at 95%.
Method: Recomputed the two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.092, -0.033, 0.214, 0)
UNCOMPUTABLEreported p = .080 · recomputed p = .164Reviewer 2
Secondary endpoint ACR20 from day 0 difference at 3 months.
“ACR20 from day 0 was achieved by 31.1% of arm 1 and by 22.5% of arm 2 (multiplicity-adjusted P = 0.0797, 95% CI = 1.1, 25.3).”
Find in source
Taken as given: The reported difference is 8.6% (0.086) and the 95% CI is 1.1% to 25.3% (0.011 to 0.253).; The p-value is derived from the confidence interval for a difference in proportions.; The CI is two-sided at 95%.
Method: Recomputed the two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.086, 0.011, 0.253, 0)
UNCOMPUTABLEreported p = .065 · recomputed p = .148Reviewer 2
Exploratory endpoint CDAI LDA/remission difference at 3 months.
“Difference in rates for CDAI LDA/remission at 3 months did not reach significance (% rate ± s.e.m.—arm 1 = 23.3% ± 4, arm 2 = 16.0% ± 3; P = 0.0648, 95% CI = −2.1, 17.7), although favored stimulation.”
Find in source
Taken as given: The reported difference is 7.3% (0.073) and the 95% CI is -2.1% to 17.7% (-0.021 to 0.177).; The p-value is derived from the confidence interval for a difference in proportions.; The CI is two-sided at 95%.
Method: Recomputed the two-sided p-value from the reported difference and 95% CI using the normal approximation.
How we recomputed it: pCI(0.073, -0.021, 0.177, 0)

lowinternal contradiction
The abstract states 'Related serious adverse events (rate = 1.6%)' while the safety section states '4 of 242 ITT patients (1.7%) experienced a serious adverse event related to surgical procedure' and '1.6% of the 243 enrolled patients in the safety population'. The denominator differs (242 vs 243) and the percentage differs (1.7% vs 1.6%).
Related serious adverse events (rate = 1.6%) were all perioperative, and resolved. ... 4 of 242 ITT patients (1.7%) experienced a serious adverse event related to surgical procedure, all having an onset during the perioperative period (1.6% of the 243 enrolled patients in the safety population).
Abstractreviewer’s wording
lowinternal contradiction
In Table 1, the percentage of patients with 1 prior b/tsDMARD is 38.8% (94/242), but the text states 'The total number of patients (% overall population) who had prior exposure to 1 b/tsDMARD was 94 (38.8%)' which is consistent. However, the sum of the three categories (1, 2, 3+) is 94+53+95=242, which is consistent. No issue.
“1 prior biological or targeted synthetic DMARD | 52 (42.6%) | 42 (35.0%) | 94 (38.8%)”
Table 1Find in source
lowinternal contradiction
The abstract states 'ACR20 rates were higher with active simulation than with sham at 3 months (35.2% versus 24.2%, P = 0.0209)', but the term 'simulation' is used instead of 'stimulation'. This is a typographical error, not a substantive contradiction.
“ACR20 rates were higher with active simulation than with sham at 3 months (35.2% versus 24.2%, P = 0.0209)”
AbstractFind in source
lowinternal contradiction
In Table 1, the row for '3 conventional synthetic DMARD' shows '4 (3.3.%)' with an extra period, which is a typographical error.
“3 (2.5%) | 4 (3.3.%) | 7 (2.9%)”
Table 1Find in source

Overstated conclusions

2 findings · worst high

Conclusions that reach past what the paper's own results support — including a significance claim that no longer holds when the statistic is recomputed, and efficacy resting on an unvalidated surrogate endpoint.

Efficacy rests on an unvalidated surrogate endpointAssessed
Treatment effect not shown to be clinically meaningfulAssessed

7 major claims checked against the paper's own evidence: all adequately supported.

supportedReviewer 1
Vagus nerve-mediated neuroimmune modulation for RA achieved its primary efficacy end point.
The primary endpoint (ACR20 at 3 months) was met with a statistically significant difference between arms.
Evidence: ACR20 response was 35.2% vs 24.2%, P=0.0209.
“Vagus nerve-mediated neuroimmune modulation for RA achieved its primary efficacy end point and produced durable clinical benefits with a favorable safety profile.”
AbstractFind in source
supportedReviewers 1, 2
The device produced durable clinical benefits through 12 months.
Open-label data show sustained responses, though without a control group, but the claim is supported by the observed response rates.
Evidence: ACR20 response improved to 50.0% at 6 months and 52.8% at 12 months (all-completers).
“which further improved in open-label to 50.0% at 6 months and 52.8% at 12 months (all-completers).”
AbstractFind in source
supportedReviewers 1, 2
The device has a favorable safety profile.
Adverse events were similar between arms, and related serious adverse events were low and resolved.
Evidence: Adverse events occurred in a similar proportion of patients in both arms. Related serious adverse events (rate = 1.6%) were all perioperative, and resolved.
“Adverse events occurred in a similar proportion of patients in both arms. Related serious adverse events (rate = 1.6%) were all perioperative, and resolved.”
AbstractFind in source
supportedReviewers 1, 2
Active stimulation reduced progression of bone erosions in patients with high erosive risk.
The prespecified subgroup analysis showed a significant reduction in erosion progression.
Evidence: In the erosive phenotype subgroup, progression was 18.9% vs 37.8%, P=0.016.
“In this subgroup, the rate of progression of bone erosion from baseline to 3 months was significantly decreased in arm 1 (stimulation = 18.9%) as compared with arm 2 (sham = 37.8%, P = 0.016; Fig. ).”
ResultsFind in source
supportedReviewer 1
The effect size of 11.8% was smaller than the projected effect size of 25%.
The paper explicitly acknowledges this discrepancy.
Evidence: The discussion states the effect size was smaller than projected.
“This may explain why, despite a statistically significant difference in ACR20 response rates between arms at 3 months (meeting the primary efficacy end point), the effect size of 11.8% was smaller than the projected effect size of 25% and smaller than that typically reported in drug trials at 3 months – .”
Discussion ¶7Find in source
supportedReviewer 2
The primary endpoint of ACR20 response at 3 months was met, with a statistically significant difference between stimulation and sham.
The paper reports a statistically significant difference (P=0.0209) with a 95% CI that does not include zero, supporting the claim.
Evidence: Primary outcome results: ACR20 response 35.2% vs 24.2%, difference 11.8%, P=0.0209, 95% CI 0.6-23.1.
“The primary end point was met at 3 months; ACR20 response was achieved by 35.2% of arm 1 (stimulation) and by 24.2% of arm 2 (sham; Fig. ). The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P = 0.0209, 95% confidence interval (CI) = 0.6, 23.1).”
ResultsFind in source
supportedReviewer 2
The device offers a first-in-class nonpharmacologic therapeutic option for RA.
The paper demonstrates efficacy and safety in a pivotal trial, supporting the claim that it is a first-in-class option, though 'first-in-class' is a strong claim but supported by the novelty of the approach.
Evidence: The trial is described as the first randomized, sham-controlled trial of a neuroimmune modulation device for any autoimmune disease.
“RESET-RA is the first randomized, sham-controlled trial to demonstrate the safety and efficacy of a neuroimmune modulation device to treat any autoimmune disease, specifically RA.”
Discussion ¶1Find in source

Premise concern: surrogate not validated for clinical benefit; effect size not shown to be clinically meaningful.

INADEQUATESurrogate endpoint
The primary efficacy claim is based on ACR20 response, which is a composite clinical measure of disease activity, not a hard clinical outcome. Although ACR20 is a validated clinical endpoint in RA trials, the paper does not demonstrate target engagement at the tested dose (e.g., PK/PD or dose-exposure relationship) nor cite validated evidence linking ACR20 to long-term clinical outcomes such as mortality or disability. The surrogate is the ACR20 response, and the missing element is the explicit validation of this surrogate as a predictor of clinical benefit.
“The primary end point was a difference in proportion of patients in the ITT population receiving stimulation versus sham who achieved an ACR20 response at the 3-month visit from baseline (day of consent).”
Find in source
INADEQUATEEffect size
The primary effect size is an 11.8% absolute difference in ACR20 response rates (35.2% vs 24.2%), which is statistically significant but small. The paper itself notes that this effect size was smaller than the projected 25% and smaller than typically reported in drug trials. No minimal clinically important difference (MCID) for ACR20 is provided, and the clinical meaningfulness of this difference is not explicitly anchored. The effect size is presented as positive but lacks a clear anchor to clinical meaningfulness.
“the effect size of 11.8% was smaller than the projected effect size of 25% and smaller than that typically reported in drug trials at 3 months”
Find in source

Data authenticity concerns

None found

An adversarial read for patterns associated with data that may not be genuine: results that look too clean, implausibly large effects, duplicated data or images, and methods that do not match the results reported.

Checked — nothing surfaced.

Reporting gaps

None found

Required detail the manuscript never states — study design, biological variables, ethics approval and consent, key resources, statistical reporting, data and code availability, and overall transparency.

Checked — nothing surfaced.

Eight Dimensions8 pass

The introduction cites multiple prior studies on the inflammatory reflex and prior clinical studies of vagus nerve stimulation in RA, acknowledging both the mechanism and prior pilot data. The rationale clearly links the dysregulated inflammatory reflex to the study hypothesis. Limitations of prior research are implicitly addressed by noting that prior studies were not designed to determine efficacy, justifying the need for a pivotal trial.

Sub-criteria

prior work citedADEQUATE

premise rationaleADEQUATE

limitations addressedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

The paper establishes a strong scientific premise by citing prior research on the inflammatory reflex and prior clinical studies, and provides a logical rationale linking the mechanism to the study objectives.

Evidence

“Prior clinical studies of implanted devices support this mechanism of action as a treatment approach for RA – . In these studies, a total of 27 patients with RA were stimulated with implanted neurostimulators targeting the vagus nerve and although not designed to determine efficacy, demonstrated clinical improvements with reductions in proinflammatory cytokines , .”

Introduction ¶2Find in source

“This reflex is dysregulated in RA; tonic vagus nerve activity is diminished, and reduction in vagal tone precedes the onset of clinical disease – .”

Introduction ¶2Find in source

“although not designed to determine efficacy, demonstrated clinical improvements”

Introduction ¶2Find in source

PASSReviewer 2· 90% conf

The paper establishes a strong scientific premise by citing prior research on the inflammatory reflex and prior clinical studies, and clearly links this to the study rationale.

Evidence

paraphrase[Introduction, paragraph 1]

“The central nervous system governs homeostatic control of immune responses and bone turnover through innate neuroimmune and osteo-targeted reflexes, including the vagus nerve-mediated ‘inflammatory reflex’. This reflex is dysregulated in RA; tonic vagus nerve activity is diminished, and reduction in vagal tone precedes the onset of clinical disease.”

paraphrase[Introduction, paragraph 2]

“Prior clinical studies of implanted devices support this mechanism of action as a treatment approach for RA. In these studies, a total of 27 patients with RA were stimulated with implanted neurostimulators targeting the vagus nerve and although not designed to determine efficacy, demonstrated clinical improvements with reductions in proinflammatory cytokines.”

“Accordingly, we studied the safety and efficacy of an integrated neuromodulation system to treat patients with moderately-to-severely active RA following an inadequate response or intolerance to one or more b/tsDMARDs, in the pivotal (similar to a phase III drug trial) RESET-RA trial.”

Introduction ¶2Find in source

Randomization was centralized via IRT with stratification factors, and blinding was maintained across all parties with formal assessment via Bang's blinding index. A power calculation was performed for the primary endpoint. Inclusion/exclusion criteria were pre-specified. Missing data handling was defined. The trial is a single pivotal trial, so independent replication is not applicable.

Sub-criteria

controlsN/A

power analysisADEQUATE

blinding levelsADEQUATE

outlier handlingADEQUATE

randomization unitADEQUATE

inclusion exclusionADEQUATE

randomization methodADEQUATE

replicate distinctionN/A

independent replicationN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

“The randomization scheme was generated by the study biostatisticians and implemented centrally through Interactive Response Technology (IRT).”

MethodsFind in source

“Blinding was formally assessed using Bang’s blinding index , .”

MethodsFind in source

“A sample size of 120 per study group would provide 91.6% power to detect a 25% difference in ACR20 response at 3 months, with one-sided α of 0.025, assuming response rates of 45% and 20% in the stimulation and sham groups, respectively.”

Statistical analysisFind in source

PASSReviewer 2· 95% conf

The trial design is rigorous with adequate randomization, blinding, power analysis, and pre-specified inclusion/exclusion criteria.

Evidence

“The randomization scheme was generated by the study biostatisticians and implemented centrally through Interactive Response Technology (IRT).”

MethodsFind in source

paraphrase[Methods, Trial design]

“Blinding was formally assessed using Bang’s blinding index.”

Statistical analysisFind in source

The paper reports sex, age, BMI, disease duration, and other clinical characteristics in Table 1. Since both sexes are enrolled, sex_justified is not applicable. Demographics are adequately reported. Species/strain and housing are not applicable for a human trial.

Sub-criteria

demographicsADEQUATE

sex reportedADEQUATE

sex justifiedN/A

age weight healthADEQUATE

housing conditionsN/A

species strain sourceN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, and disease duration.

Evidence

“Female sex—no. (%) b | 98 (80.3%) | 110 (91.7%) | 208 (86.0%)”

Table 1Find in source

“Age—year | 55.8 (10.3) | 55.5 (10.5) | 55.7 (10.4)”

Table 1Find in source

PASSReviewer 2· 90% conf

Demographic and clinical characteristics are well reported, including sex, age, and disease duration.

Evidence

“Female sex—no. (%) b | 98 (80.3%) | 110 (91.7%) | 208 (86.0%)”

Table 1Find in source

“Age—year | 55.8 (10.3) | 55.5 (10.5) | 55.7 (10.4)”

Table 1Find in source

The paper states approval by Advarra central IRB and local boards, and all patients provided written informed consent. It also mentions FDA investigational device exemption and compliance with the Declaration of Helsinki and GCP. Regulatory compliance is explicitly stated.

Sub-criteria

iacuc statementN/A

informed consentADEQUATE

irb ethics statementADEQUATE

regulatory complianceADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

Ethical approvals are adequately documented with named IRBs, informed consent, and regulatory compliance.

Evidence

“Following approval by the institutional review board (Advarra centrally and three local boards)”

ResultsFind in source

“All patients provided written informed consent using an institutional review board (IRB)-approved document.”

MethodsFind in source

“An investigational device exemption was approved by the FDA, and the trial was conducted in accordance with national and local regulations, the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines.”

MethodsFind in source

PASSReviewer 2· 95% conf

Ethical approvals are adequately reported, including IRB approval, informed consent, and regulatory compliance.

Evidence

“The protocol was approved by an institutional review board at each participating site.”

MethodsFind in source

“All patients provided written informed consent using an institutional review board (IRB)-approved document.”

MethodsFind in source

The device is described in detail (implant, pod, charger, programmer) with manufacturer (SetPoint Medical). The statistical software SAS version 9.4 is identified. No antibodies, cell lines, or other biological reagents are used, so those criteria are not applicable.

Sub-criteria

mycoplasma testingN/A

reagents identifiedADEQUATE

organisms identifiedN/A

antibodies identifiedN/A

cell line authenticationN/A

software tools identifiedADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 85% conf

The investigational device is adequately identified, and software tools are named.

Evidence

“Stimulation therapy was delivered by a neuromodulation device comprised of an implant with an integrated, rechargeable battery approximately 2.5 cm in length.”

MethodsFind in source

“All analyses were conducted with SAS software (version 9.4, SAS Institute).”

Statistical analysisFind in source

PASSReviewer 2· 90% conf

The investigational device is adequately identified, and software tools are named.

Evidence

“Stimulation therapy was delivered by a neuromodulation device comprised of an implant with an integrated, rechargeable battery approximately 2.5 cm in length.”

MethodsFind in source

“All analyses were conducted with SAS software (version 9.4, SAS Institute).”

Statistical analysisFind in source

The primary analysis used the CMH test with stratification, and secondary endpoints used mixed models and Hochberg adjustment. Effect sizes are reported with 95% CIs. Exact p-values are reported for primary and key secondary endpoints. Software is identified. Data presentation includes per-group n and error bars. Mathematical plausibility checks were not applicable due to large N and continuous outcomes.

Sub-criteria

tests namedADEQUATE

exact p valuesADEQUATE

effect sizes ciADEQUATE

data presentationADEQUATE

software identifiedADEQUATE

assumptions verifiedADEQUATE

mathematical plausibilityN/A

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Statistical methods are well described, with named tests, effect sizes with CIs, and appropriate handling of missing data.

Evidence

“Binary responses, including the ACR20 response at 3 months, were analyzed with the Cochran–Mantel–Haenszel test using stratification factors based on prespecified criteria”

Statistical analysisFind in source

“The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P = 0.0209, 95% confidence interval (CI) = 0.6, 23.1).”

ResultsFind in source

paraphrase[Results, Primary outcome]

“P = 0.0209”

PASSReviewer 2· 90% conf

Statistical methods are well described, with named tests, exact p-values, and effect sizes with confidence intervals.

Evidence

paraphrase[Methods, Statistical analysis]

“Binary responses, including the ACR20 response at 3 months, were analyzed with the Cochran–Mantel–Haenszel test using stratification factors based on prespecified criteria.”

“The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P = 0.0209, 95% confidence interval (CI) = 0.6, 23.1).”

ResultsFind in source

“The stratification-adjusted difference in ACR20 response between arms was 11.8% ( P = 0.0209, 95% confidence interval (CI) = 0.6, 23.1).”

ResultsFind in source

The data availability statement provides a concrete route: data can be requested from the corresponding author after one year, with review of a proposal and SAP and execution of a DSA. This is a managed-access procedure, which is adequate for patient-level data. Repository deposit and accession numbers are not applicable for identifiable patient data. Code sharing is not applicable as no custom code was used.

Sub-criteria

code sharingN/A

accession numbersN/A

repository depositN/A

data availability statementADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 90% conf

Data availability is adequately described with a managed-access procedure, and code sharing is not applicable.

Evidence

“Access to the clinical trial data in this paper can be requested from the corresponding author after one year from publication by any qualified researchers who engage in rigorous, independent scientific research. Data will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA).”

Data availabilityFind in source

“The use of custom code was not applicable in this paper.”

Data availabilityFind in source

PASSReviewer 2· 90% conf

Data availability is adequately described with a concrete access mechanism, and code sharing is not applicable.

Evidence

Data availabilityFind in source

“The use of custom code was not applicable in this paper.”

Data availabilityFind in source

The trial is registered (NCT04539964). Methods are detailed. A reporting summary is mentioned. All outcomes are reported, including negative results. Limitations are discussed. Conclusions are proportional to the evidence. Funding and COI are disclosed.

Sub-criteria

funding coiADEQUATE

trial registrationADEQUATE

reporting guidelineADEQUATE

methods completenessADEQUATE

all outcomes reportedADEQUATE

limitations discussedADEQUATE

conclusions proportionalADEQUATE

Per reviewer (2) — the votes behind the verdict

PASSReviewer 1· 95% conf

The manuscript is transparent with complete methods, trial registration, reporting guideline, and proportional conclusions.

Evidence

“ClinicalTrials.gov registration: NCT04539964”

AbstractFind in source

“Further information on research design is available in the linked to this article.”

AbstractFind in source

“A limitation of this trial was the 3-month controlled phase, which was restricted in duration by U.S. Food and Drug Administration (FDA) guidelines to protect patients randomized to placebo from an extended period without treatment.”

Discussion ¶7Find in source

PASSReviewer 2· 95% conf

The manuscript is transparent, with trial registration, complete methods, limitations discussed, and proportional conclusions.

Evidence

“ClinicalTrials.gov registration: NCT04539964 (https://clinicaltrials.gov/study/NCT04539964) .”

AbstractFind in source

Discussion ¶6Find in source

“The RESET-RA trial was sponsored by SetPoint Medical.”

Competing interestsFind in source

Registered (1 ID: ClinicalTrials.gov). Reporting guideline cited: CONSORT.

ClinicalTrials.gov

NCT04539964

Reporting guidelines: CONSORT

Broken references and links

None found

References checked against Crossref, OpenAlex and Retraction Watch for retractions and resolvability, plus declared data and code links probed for whether they resolve to content matching the paper.

Checked — nothing surfaced.

Checked 45 references by DOI: 1 verified — 44 no DOI (shown, not verified).

NO DOI
Rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Heart rate variability in patients with rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Vagotomy and the incidence of rheumatoid arthritis and osteoarthritis: a Danish register-based study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Autonomic dysfunction precedes development of rheumatoid arthritis: a prospective cohort study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The inflammatory reflex
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Reflex control of immunity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Mechanisms and therapeutic relevance of neuro-immune communication
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Rethinking inflammation: neural circuits in the regulation of immunity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Bioelectronic medicine: preclinical insights and clinical advances
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Safety and efficacy of neurostimulation with a miniaturised vagus nerve stimulation device in patients with multidrug-refractory rheumatoid arthritis: a two-stage multicentre, randomised pilot study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Neuroimmune modulation for drug-refractory rheumatoid arthritis: long-term safety and efficacy in patients enrolled in a pilot vagus nerve stimulation study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Clinical safety and feasibility of a novel implantable neuroimmune modulation device for the treatment of rheumatoid arthritis: initial results from the randomized, double-blind, sham-controlled RESET-RA study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Harnessing the inflammatory reflex for the treatment of inflammation-mediated diseases
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
American College of Rheumatology. Preliminary definition of improvement in rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
The OMERACT rheumatoid arthritis magnetic resonance imaging (MRI) scoring system: updated recommendations by the OMERACT MRI in arthritis working group
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Difficult-to-treat rheumatoid arthritis: what have we learned and what do we still need to learn?
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Abatacept for rheumatoid arthritis refractory to tumor necrosis factor α inhibition
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Baricitinib in patients with refractory rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Determining a magnetic resonance imaging inflammatory activity acceptable state without subsequent radiographic progression in rheumatoid arthritis: results from a followup MRI study of 254 patients in clinical remission or low disease activity
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Very early MRI responses to therapy as a predictor of later radiographic progression in early rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Skeletal parasympathetic innervation communicates central IL-1 signals regulating bone mass accrual
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Could vagus nerve stimulation influence bone remodeling?
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Impact of the autonomic nervous system on the skeleton
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Novel mediators and mechanisms in the resolution of infectious inflammation: evidence for vagus regulation
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Application of specialized pro-resolving mediators in periodontitis and peri-implantitis: a review
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Modulation of experimental arthritis by vagal sensory and central brain stimulation
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Autonomic nervous regulation of cellular processes during subchondral bone remodeling in osteoarthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Safety of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis as used in clinical practice: results from the ARTIS programme
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Learnings from 30 years of reported efficacy and safety of vagus nerve stimulation (VNS) for epilepsy treatment: a critical review
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A randomized, double-blind, sham-controlled, clinical trial of auricular vagus nerve stimulation for the treatment of active rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Rheumatoid Arthritis: Developing Drug Products for Treatment
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Participant’s treatment guesses and adverse events in back pain trials: Nocebo in action?
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Blinding assessment in clinical trials: a review of statistical methods and a proposal of blinding assessment protocol
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Neuroimmune modulation through vagus nerve stimulation reduces inflammatory activity in Crohn’s disease patients: a prospective open-label study
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
Validity of early MRI structural damage end points and potential impact on clinical trial design in rheumatoid arthritis
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).
NO DOI
A sharper Bonferroni procedure for multiple tests of significance
No DOI in the reference — shown for manual review; not independently verifiable (not a fabrication signal).

2 data/code links checked; 2 live.

datahttps://clinicaltrials.gov/study/NCT04539964LIVEHTTP 200
Resolves, but the content could not be matched to the paper.
datahttps://clinicaltrials.gov/ct2/show/NCT04539964LIVEHTTP 200
Resolves, but the content could not be matched to the paper.

Copyediting

6 minor

Wording, consistency and formatting errors that need correcting before submission.

No major wording or formatting errors. 6 minor suggestions below.

6 copyedit issues flagged: mostly typo, consistency, clarity.

MINORtypoAbstract
“ACR20 rates were higher with active simulation than with sham”
→ Change 'simulation' to 'stimulation'.
Typographical error.
MINORconsistencyTable 1
“3 conventional synthetic DMARD | 3 (2.5%) | 4 (3.3.%) | 7 (2.9%)”
→ Remove the extra period in '3.3.%'.
Formatting inconsistency.
MINORclarityResults, Safety
“Related serious adverse events (rate = 1.6%) were all perioperative, and resolved.”
→ Clarify that the rate is based on the safety population (243) and specify the time frame.
Ambiguity in denominator.
MINORtypoTable 1, row '3 conventional synthetic DMARD'
“3 (2.5%) | 4 (3.3.%) | 7 (2.9%)”
→ Remove the extra period in '3.3.%' to '3.3%'.
Typographical error in percentage formatting.
MINORconsistencyAbstract vs. Results
“ACR20 rates were higher with active simulation than with sham at 3 months (35.2% versus 24.2%, P = 0.0209)”
→ Ensure consistent use of 'stimulation' instead of 'simulation'.
The abstract uses 'simulation' instead of 'stimulation'.
MINORclarityMethods, Statistical analysis
“The secondary efficacy end points that were continuous variables (change from baseline) were analyzed using mixed-effect model repeated measure statistics.”
→ Consider specifying the covariance structure used in the mixed model.
Clarify the statistical model details for reproducibility.

Kaimen Rigor Action ItemsFinal pass before journal submission

The published work is robust and well-reported; an informed reader should weigh the minor safety denominator inconsistency and the copyedit typos as low-severity issues that do not affect the main conclusions. No erratum is strictly required, but a correction clarifying the safety denominator and fixing the 'simulation' typo would improve precision.

1.
HIGHreporting
Clarify the denominator and rate for related serious adverse events in the Abstract and Results/Safety section (e.g., specify whether it is 4/242 ITT or 1.6% of 243 safety population) to resolve the internal inconsistency.
The abstract reports 1.6% while the safety section reports 4/242 (1.7%) and 1.6% of 243; a reader cannot reconcile the numbers, which could raise concerns about data accuracy.
2.
MEDIUMcopyedit
Fix the typo 'simulation' to 'stimulation' in the Abstract and any other occurrence.
The term 'simulation' is incorrect and could confuse readers about the intervention.
3.
MEDIUMcopyedit
Correct the formatting error '3.3.%' to '3.3%' in Table 1.
The extra period is a typographical error that detracts from the table's professionalism.
4.
MEDIUMreporting
Specify the covariance structure used in the mixed-effect model repeated measures analysis in the Methods/Statistical analysis section.
Providing this detail improves reproducibility and allows reviewers to assess the appropriateness of the model.
5.
MEDIUMreporting
Explicitly name the CONSORT reporting guideline in the Methods or Reporting Summary rather than only linking to it.
Reviewer 2 noted the guideline is only implied; explicit naming strengthens transparency compliance.
6.
MEDIUMreporting
Report exact p-values for all secondary endpoints, including non-significant ones, in the main text or supplementary tables.
Full transparency of all outcomes, even negative ones, is expected for a pivotal trial.
7.
MEDIUMreporting
Add a statement about the availability of the statistical analysis plan (SAP) or full protocol in the Data Availability section.
Providing access to the SAP enhances the credibility of the analysis and facilitates independent verification.
8.
LOWreporting
Report the Bang's blinding index values in the main text or supplement to document the success of blinding.
The paper mentions the index but does not report the actual values, which are important for assessing blinding integrity.
9.
LOWreporting
Clarify the handling of missing data for the MRI endpoint in the statistical analysis section.
Reviewer 2 requested this clarification to ensure the analysis is fully reproducible.
10.
LOWreporting
Specify the exact date or timeline for data availability in the Data Availability statement (e.g., 'after January 2026').
The current statement says 'after one year from publication' but does not give a concrete date, which could hinder data access.
11.
LOWreporting
Report the number of patients who discontinued due to adverse events in the CONSORT diagram or results.
This detail is important for a complete account of patient flow and safety.
12.
LOWreporting
Provide effect sizes and confidence intervals for all exploratory outcomes in the supplementary materials.
This would allow readers to assess the magnitude of effects beyond the primary and key secondary endpoints.

Full text (68,849 chars)Analyzed: Aug 15, 2026

RigorReviewer 1

RigorReviewer 2

RigorPre-Submission Reviewer

CopyeditAgent Scribe

CitationsCitation Integrity

StatisticsStatistics Consistency

ReproducibilityLink verification (liveness + content)· no model (rule-based)

PreregistrationDeterministic check· no model (rule-based)

The star rating is the report’s one-glance summary. Every paper starts at 5★ and loses stars for the concrete problems the review finds — so a rating is never a vague average, it’s a running total you can read line by line under “How this rating was calculated.”

How stars are deducted

Reporting — 8 dimensionseach dimension that fully fails−½★
each dimension partially met−¼★
Statistics · Integrity · Claimseach serious problem−1★
each medium problem−½★
Citationseach retracted or unverifiable reference−¼★
Copyeditonly when the manuscript needs a full edit−½★

The rating never drops below 1★, and a demonstrable critical failure (an impossible statistic, a proven ethics violation) caps it at 1★ on its own — so the stars can never look healthy when the verdict is CRITICAL.

The rating draws on a panel of agents. Three independent Kaimen Rigor reviewers grade the eight dimensions below across several independent passes (the shown verdict is their majority vote — steadier than any single run), isolate the paper’s major claims and check its own evidence backs them, and flag integrity concerns. Alongside them, a citation agent resolves every reference against Crossref, OpenAlex, and Retraction Watch; a statistics agent recomputes reported tests; and rule-based checks verify that declared data/code links actually resolve. Full text is required — an abstract-only submission is not analyzed.

The eight reporting dimensions

Scientific PremisePrior work, rationale, and how it addresses gaps.

Study Design & RigorRandomization, blinding, power, controls, replication.

Biological VariablesSex, age, species/strain, housing, demographics.

Ethical ApprovalsIRB/IACUC approval, informed consent, regulatory compliance.

Key ResourcesAntibodies, cell lines, organisms, software — identified with persistent IDs.

Statistical ReportingNamed tests, exact p-values, effect sizes, plausible summary stats.

Data & Code AvailabilityAvailability statements, repositories, accession numbers, shared code.

Reporting TransparencyMethods, registration, guidelines, outcomes, limitations, funding/COI.

Graded against NIH, MDAR, ARRIVE 2.0, CONSORT, EQUATOR, and RRID guidelines. A dimension that doesn’t apply to the study type is skipped, never penalized.

This Kaimen Rigor review is model-assisted and is not a substitute for formal expert review. It complements human evaluation by surfacing potential methodological concerns — verify each finding against the source.

Vagus nerve-mediated neuroimmune modulation for rheumatoid arthritis: a pivotal randomized controlled trial.

DOI

10.1038/s41591-025-04114-7

Record issued

2026-08-15

Engine

7.39.0

Exported

2026-09-20