CoChat
Sign Up
Cited by 114Stress Responses and CortisolSystemic Lupus Erythematosus ResearchAdrenal Hormones and Disorders

Increase of sympathetic outflow measured by neuropeptide Y and decrease of the hypothalamic-pituitary-adrenal axis tone in patients with systemic lupus erythematosus and rheumatoid arthritis: another example of uncoupling of response systems

Open access
Härle, P, Straub, R H, Wiest, R, Mayer, A, Schölmerich, J, Atzeni, F, Carrabba, M, Cutolo, M +1 more·2006·Annals of the Rheumatic Diseases
DOI 10.1136/ard.2005.038059PMC PMC1797997
Open this paper in CoChat — free accountOpen PDF

Abstract

Objective To study in parallel the outflow of the sympathetic nervous system (SNS) and the hypothalamic-pituitary adrenal (HPA) axis tone in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).Methods 32 patients with SLE, 62 with RA, and 65 healthy subjects (HS) were included. To measure the tone of the HPA axis, plasma ACTH and serum cortisol were determined. Serum neuropeptide Y (NPY) was used to evaluate the sympathetic outflow.Results Patients with SLE had increased NPY levels in comparison with HS, irrespective of prior prednisolone treatment (p<0.001). For patients with RA, only those with prednisolone treatment had increased NPY levels in comparison with HS (p = 0.016). Daily prednisolone dose correlated positively with serum NPY in RA (R(Rank) = 0.356, p = 0.039). In contrast, plasma ACTH levels were generally decreased significantly in comparison with HS in SLE with prednisolone, and in RA with/without prednisolone. Similarly, serum cortisol levels were also decreased in SLE with/without prednisolone, and in RA with prednisolone. The NPY/ACTH ratio was increased in SLE and RA, irrespective of prior prednisolone treatment. The NPY/cortisol ratio was increased in SLE with/without prednisolone, and in RA with prednisolone. Twelve weeks' anti-TNF antibody treatment with adalimumab did not decrease NPY levels in RA, irrespective of prednisolone treatment.Conclusions An increased outflow of the SNS was shown and a decreased tone of the HPA axis in patients with SLE and RA. Low levels of cortisol in relation to SNS neurotransmitters may be proinflammatory because cooperative anti-inflammatory coupling of the two endogenous response axes is missing.

AI snapshot

Written from the paper’s full text.

TL;DR

In patients with SLE and RA, serum neuropeptide Y indicated increased sympathetic outflow while ACTH/cortisol indicated reduced hypothalamic-pituitary-adrenal axis tone, producing increased NPY/ACTH and NPY/cortisol ratios. This uncoupling was present with or without prednisolone in SLE and mainly in prednisolone-treated RA, and 12 weeks of adalimumab did not reduce NPY levels.

Key findings

  • Patients with SLE had increased NPY levels versus healthy subjects, irrespective of prior prednisolone treatment (p<0.001); in RA, only prednisolone-treated patients had increased NPY versus healthy subjects (p=0.016), and daily prednisolone dose correlated positively with serum NPY in RA (R Rank=0.356, p=0.039).
  • Plasma ACTH was decreased versus healthy subjects in SLE with prednisolone and in RA with or without prednisolone; serum cortisol was decreased in SLE with or without prednisolone and in RA with prednisolone.
  • The NPY/ACTH ratio was increased in SLE and RA irrespective of prior prednisolone treatment; the NPY/cortisol ratio was increased in SLE with or without prednisolone and in RA with prednisolone.
  • Twelve weeks of anti-TNF treatment with adalimumab did not decrease NPY levels in RA, irrespective of prednisolone treatment, and neither NPY/ACTH nor NPY/cortisol ratios changed during treatment.

Methods

  • The study included 32 patients with SLE, 62 patients with RA, and 65 healthy subjects; subgroups were matched according to age and sex. Blood was drawn between 08:00 and 10:00, and serum NPY, plasma ACTH, and serum cortisol were measured by immunoassays.
  • Some patients with RA (16 with and 16 without parallel prednisolone) received adalimumab 40 mg subcutaneously every other week for 12 weeks plus stable methotrexate; blood was drawn at baseline and at weeks 2, 6, and 12.
  • Group medians were compared by Mann-Whitney tests, correlations by Spearman rank analysis, and changes over time by Friedman tests; p<0.05 was significant.

Limitations

  • Stated in the paper: norepinephrine was not measured because of expected strong bias from prolonged storage, since norepinephrine is more labile than NPY; the authors also note that NPY may not be the ideal measure in older patients when SNS activity is only increased to a small extent.
  • Evident from the text: the main SLE/RA versus healthy-subject comparisons are cross-sectional, so temporal or causal direction cannot be established; prednisolone groups were not randomized, and the adalimumab analysis was a small RA subset (16 with and 16 without prednisolone) with no placebo control described in this paper.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1136/ard.2005.038059

Cites

59 of 59 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 12 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Daily prednisolone dose correlated positively with serum NPY in patients with RA (Spearman rank R=0.356, p=0.039).

    “Daily prednisolone dose correlated positively with serum NPY in RA (R Rank = 0.356, p = 0.039).”
    • Also stated in: § DISCUSSION · boosted
      “Clearly, the prednisolone dose correlated with NPY serum levels in patients with RA but not in patients with SLE (figs 1C and D).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among patients with RA, only those with prior prednisolone treatment had increased serum NPY levels compared with healthy subjects (p=0.016).

    “For patients with RA, only those with prednisolone treatment had increased NPY levels in comparison with HS (p = 0.016).”
    • Also stated in: § DISCUSSION · plain
      “In RA, only patients with prior prednisolone had increased NPY serum levels in comparison with healthy subjects (fig 1B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Twelve weeks of anti-TNF antibody treatment with adalimumab did not decrease serum NPY levels in patients with RA, irrespective of prednisolone treatment.

    “Twelve weeks' anti-TNF antibody treatment with adalimumab did not decrease NPY levels in RA, irrespective of prednisolone treatment.”
    • Also stated in: § DISCUSSION · plain
      “Using the Friedman test statistics, 12 weeks of anti-TNF treatment did not change NPY serum levels, irrespective of prednisolone treatment (fig 4).”
    Quote in the paperSubstantial claim
  • Findingown data

    Patients with SLE had increased serum NPY levels compared with healthy subjects, irrespective of prior prednisolone treatment (p<0.001).

    “Patients with SLE had increased NPY levels in comparison with HS, irrespective of prior prednisolone treatment (p,0.001).”
    • Also stated in: § DISCUSSION · boosted
      “Figure 1 demonstrates higher NPY serum levels in patients with SLE than in HS, irrespective of prednisolone treatment (fig 1A).”
    Quote in the paperSubstantial claim
  • Findingown data

    The serum NPY/serum cortisol ratio was increased in SLE patients both with and without prior prednisolone treatment.

    “The NPY/cortisol ratio was increased in SLE with/without prednisolone, and in RA with prednisolone.”
    • Also stated in: § Relation of NPY serum levels and HPA axis hormones · plain
      “The ratio of NPY/cortisol was increased in both SLE patient groups, irrespective of prednisolone treatment (fig 3C).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 8

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Plasma NPY levels did not differ between male and female patients with or without prednisolone treatment.

    “Plasma NPY levels did not differ between male and female patients with or without prednisolone (data not shown).”
    • Also stated in: § Relation of NPY serum levels and HPA axis hormones · plain
      “The above-mentioned ratios did not differ between male and female patients with or without prednisolone (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Neither the serum NPY/plasma ACTH ratio nor the serum NPY/serum cortisol ratio changed during 12 weeks of anti-TNF treatment in patients with RA.

    “In addition, neither the ratio of serum NPY/plasma ACTH nor the ratio of serum NPY/serum cortisol changed during 12 weeks of anti-TNF treatment (data not shown).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Patients without prednisolone received no glucocorticoids for 6 months before study entry, whereas patients with prednisolone had stable treatment over several weeks before study entry.

    “None of the patients without prednisolone received glucocorticoids during a period of 6 months before study entry, whereas patients with prednisolone had stable treatment over several weeks before study entry.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    An increased SNS tone would support atherosclerosis in patients with chronic inflammatory diseases.

    “In addition, an increased SNS tone would support atherosclerosis in patients with chronic inflammatory diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cortisol and norepinephrine cooperate at a molecular level, and this permissive effect of cortisol is due to beta adrenoceptor up regulation and stabilisation of the cAMP/protein kinase A/CREB signalling pathway.

    “This permissive effect of cortisol is due to b adrenoceptor up regulation and stabilisation of the cyclic AMP (cAMP)/protein kinase A/ cAMP responsive element binding protein signalling pathway.30”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [30] Schramm, 2000, beta-Adrenergic relaxation of rabbit tracheal smooth muscle: a receptor deficit that improves with corticosteroid administration, J Pharmacol Exp Ther source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The study was approved by the ethics committee of the University Hospital of Regensburg, Germany, and the adalimumab study was approved by the ethics committee of L Sacco University Hospital, Italy.

    “The study was approved by the ethics committee of the University Hospital of Regensburg, Germany, and for the adalimumab study, approval was obtained from the ethics committee of L Sacco University Hospital, Italy.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For all assays used, intra-assay and inter-assay coefficients of variation were below 10%.

    “For all assays, intraassay and interassay coefficients of variation were below 10%.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    An increased outflow of the sympathetic nervous system and a decreased tone of the HPA axis are present in patients with SLE and RA.

    “An increased outflow of the SNS was shown and a decreased tone of the HPA axis in patients with SLE and RA.”
    • Also stated in: § DISCUSSION · boosted
      “Using NPY as a reliable read-out measure of the SNS activity, we were able to demonstrate an increased SNS outflow in relation to the HPA axis tone in all patients with SLE and in patients with RA treated with prednisolone.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In chronic inflammatory diseases such as SLE or RA the HPA axis alters markedly, with inadequate ACTH secretion relative to circulating cytokines and inappropriately low spontaneous and stimulated cortisol secretion in relation to inflammation.

    “In chronic inflammatory diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) the HPA axis alters markedly : (a) secretion of adrenocorticotropic hormone (ACTH) relative to circulating cytokines is inadequate 7 ; (b) patients have inappropriately low sponta- neous and stimulated cortisol secretion in relation to inflammation”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Straub, 2002, Inadequately low serum levels of steroid hormones in relation to IL-6 and TNF in untreated patients with early rheumatoid arthritis and reactive arthritis, Arthritis Rheum source

      Not checked in the free run.

    • cites [8] Gudbjornsson, 1996, Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids, J Rheumatol

      Not checked in the free run.

    • cites [9] Crofford, 1997, Circadian relationships between interleukin (IL)-6 and hypothalamic- pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis, J Clin Endocrinol Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NPY is an excellent indicator of sympathetic activity, being more stable and having a significantly longer half-life in plasma than norepinephrine.

    “NPY is an excellent indicator of sympathetic activity, 34 which is more stable and has a significantly longer half life in plasma.35”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [34] Morris, 1986, Increases in plasma neuropeptide Y concentrations during sympathetic activation in man, J Auton Nerv Syst source

      Not checked in the free run.

    • cites [35] Pernow, 1986, Plasma neuropeptide Y-like immunoreactivity and catecholamines during various degrees of sympathetic activation in man, Clin Physiol source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Subgroup analyses comparing patient groups with healthy subjects were matched according to age and sex.

    “The subgroups were matched according to age and sex (table 1).”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    Some studies have indicated that patients with chronic inflammatory diseases have an increased activity of the sympathetic nervous system.

    “Some studies have indicated that patients with chronic inflammatory diseases have an increased activity of the SNS.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [16] Leden, 1983, Autonomic nerve function in rheumatoid arthritis of varying severity, Scand J Rheumatol source

      Not checked in the free run.

    • cites [17] Kuis, 1996, The autonomic nervous system and the immune system in juvenile rheumatoid arthritis, Brain Behav Immun source

      Not checked in the free run.

    • cites [18] Perry, 1989, Altered autonomic function in patients with arthritis or with chronic myofascial pain, Pain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Release of cortisol is typically coupled to release of norepinephrine, which leads to stronger signalling through the beta adrenoceptor.

    “Release of cortisol is typically coupled to release of norepinephrine, which leads to stronger signalling through the b adrenoceptor; several studies have shown cooperation of cortisol and norepinephrine at a molecular level.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [22] Oikarinen, 1984, Modulation of glucocorticoid receptor activity by cyclic nucleotides and its implications on the regulation of human skin fibroblast growth and protein synthesis, Biochim Biophys Acta source

      Not checked in the free run.

    • cites [23] Gruol, 1986, Cyclic AMP-dependent protein kinase promotes glucocorticoid receptor function, J Biol Chem source

      Not checked in the free run.

    • cites [24] Nakada, 1987, Glucocorticoid regulation of beta-adrenergic receptors in 3T3-L1 preadipocytes, Mol Pharmacol

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In all subjects, blood was drawn between 08:00 and 10:00 in the morning.

    “In all subjects, blood was drawn between 08:00 and 10:00 in the morning when the patients visited the outpatient clinic.”
    Quote in the paperNot a substantial claim
14 of 14

  • The paper relies on this without support.

    Serum levels of adrenal hormones are largely independent of sex.

    “Because serum levels of adrenal hormones are largely independent of sex, male and female subjects were not further separated into subgroups.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Adalimumab administration is described as both injection and infusion

    Minor

    The methods specify subcutaneous self-injections every other week, but the next sentence says the anti-TNF antibodies were infused. These describe different administration routes for the treatment.

  • Claimed age- and sex-matching conflicts with the RA control group

    Minor

    The RA group was 84% female and had a mean age of 57.7 years, whereas its purportedly matched healthy-subject group was 52% female with a mean age of 51.5 years. These reported characteristics do not support the statement that the groups were matched on both age and sex.

2 of 2

Cites

Flagged first, then by citations

12 of the 71 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Dekkers JC. Psychophysiological responsiveness in recently diagnosed patients with rheumatoid arthritis. Dordrecht: Drukkerij Dekkers, 2000, (Thesis.).
  2. Atzeni, 2004, Autoantibodies profile of rheumatoid arthritis patients during treatment with adalimumab [abstract], Ann Rheum Dis, 63, 298

Cited by

Sorted by citations

Related

Authors
Härle, P., Straub, R. H., Wiest, R., Mayer, A., Schölmerich, J., Atzeni, F., Carrabba, M., Cutolo, M., & Sarzi-Puttini, P.
Affiliations
  • University Hospital Regensburg (DE)
  • Luigi Sacco Hospital (IT)
  • University of Genoa (IT)
Corresponding author
Straub, R H
ORCID
Cutolo, M
Venue
Annals of the Rheumatic Diseases
Publisher
Elsevier BV
Published
2006-01
Volume
65
Issue
1
Pages
51-56
ISSN
0003-4967 (ISSN-L)
DOI
10.1136/ard.2005.038059
PMC
PMC1797997
OpenAlex
W2103734979
Semantic Scholar
481ff5edd6e0c0423286f6e3f087c7d8f982432f
Cited by
114
References
71
Citations by year
2025: 2 · 2024: 2 · 2023: 8 · 2022: 4 · 2021: 2 · 2020: 5 · 2019: 4 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 9 · 2014: 10 · 2013: 11 · 2012: 7
FWCI
3.48
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of the Rheumatic Diseases (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • University of Regensburg Publication Server (University of Regensburg) (acceptedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • HighWire Press Open Archive (submittedVersion)
  • University of Regensburg Publication Server (University of Regensburg)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Rheumatology › Systemic Lupus Erythematosus Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adrenal Hormones and Disorders
Keywords
sympathetic nervous system, neuropeptide Y, hypothalamic-pituitary-adrenal axis, systemic lupus erythematosus, rheumatoid arthritis, prednisolone, ACTH, cortisol, adalimumab, anti-TNF therapy, proinflammation, autoimmunity
MeSH terms
Adalimumab, Adrenocorticotropic Hormone, Adult, Antibodies, Monoclonal, Arthritis, Rheumatoid, Female, Glucocorticoids, Humans, Hydrocortisone, Hypothalamo-Hypophyseal System, Lupus Erythematosus, Systemic, Male, Middle Aged, Neuropeptide Y, Pituitary-Adrenal System, Prednisolone, Severity of Illness Index, Sympathetic Nervous System, Tumor Necrosis Factor-alpha, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review