Rheumatoid ArthritisCortRyRANCT05671627
Cortisol Circadian Rhythm in Patients With RA
An observational study of Rheumatoid Arthritis, run by National and Kapodistrian University of Athens at 1 site in Greece.
Trial summary
The European League Against Rheumatism (EULAR), acknowledging the critical issue of the complications, of long term treatment with glucocorticoids in the most recent update of the management guidelines for Rheumatoid arthritis, recommends tapering (on sustained clinical remission) of oral glucocorticoids treatment at… Read more about this study
- Who is it for?
- Ages 20 to 80 yearsHealthy volunteers can take part
- Conditions the study is for
- Rheumatoid Arthritis
- What is being tested?
- DMARDs
- How many people
- 50 participants
- Where
- 1 siteGreece
- Study dates
- 2 Feb 2022to 30 Jun 2023
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 to 80 years
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: All consecutive adult patients fulfilling the 2010 ACR/EULAR classification criteria that visit the Outpatient clinic for Rheumatology and autoimmune diseases.
Who may be able to join
- RA adult patients (fulfilling the 2010 ACR/EULAR classification criteria) who are:
- Newly -diagnosed and are going to start treatment, or
- require escalation of drug treatment due to active disease (addition of biologic or cDMARD or change of biologic with or without corticosteroids) providing that are off corticosteroid treatment for at least 6 months.
Who cannot join
- chronic kidney disease stage 3b and above,
- antineoplastic treatment,
- TSH>10 IU/lt,
- Cushing syndrome
- hypo-/hyper-parathyroidism
- estrogen replacement therapy
Show all 9Show fewer
- insulin treatment or HBA1c>7.5 %,
- BMI>35
- pregnancy
Trial locations and contacts
1 site in 1 country.
Greece1 site, 1 recruiting
- Recruiting
Laiko General Hospital
Athens, 11527
Maria Yavropoulou, M.D., 6936159517, myavropoulou@med.uoa.gr
Maria Fillipa, M.D., 6980451321, filippamariaioanna@gmail.com
About this study
Official title: An Impaired Functional Reserve of Adrenal Cortex May Associate With difficult-to Treat RA: Can a Disturbed Cortisol Circadian Rhythm Serve as a Predictor of Difficult-to-treat RA?
The European League Against Rheumatism (EULAR), acknowledging the critical issue of the complications, of long term treatment with glucocorticoids in the most recent update of the management guidelines for Rheumatoid arthritis, recommends tapering (on sustained clinical remission) of oral glucocorticoids treatment at the earliest feasible time point of therapeutic course and to the lowest daily dose, preferably <7.5mg/day (prednisone equivalent), until the final target of withdrawal is succeeded. In clinical practice, these guidelines are often difficult to follow due to the high risk of disease flares after tapering or stopping glucocorticoids administration. This inability of tapering oral glucocorticoids below 7.5mg/day of prednisone or an equivalent synthetic glucocorticoid is included in the recent definition of difficult-to-treat Rheumatoid arthritis. SΕΜΙRΑ (Steroid EliMination In Rheumatoid Arthritis) study, a double-blind, multicentre, randomised controlled trial, compared oral glucocorticoids tapering with the continuation of low dose oral glucocorticoids. The population study consisted of 259 RA patients with low disease activity on treatment with 5mg per day prednisone and tocilizumab, an anti-interleukin (IL)-6 receptor antibody. The study demonstrated that the continued-prednisone regimen provided better maintenance of disease remission than did the tapered-prednisone regimen for the study period of 24 weeks with no symptoms suggestive of AI. However, the study protocol did not include biochemical assessment of adrenocortical function.
Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in Rheumatoid arthritis. Although the underlying molecular mechanisms remain unknown, both chronic overexpression of proinflammatory cytokines and chronic stress may contribute in the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis and the target tissue glucocorticoid resistance that have been described, but not systematically studied. Thus, a precise longitudinal assessment of endogenous cortisol production may be needed for optimal management of patients with Rheumatoid arthritis. Based on the above, the investigators seek to investigate the hypothesis that an impaired functional reserve of adrenal cortex, due to chronic over-expression of pro-inflammatory cytokines and/or chronic stress may contribute to the development of Rheumatoid arthritis and/or associate with difficult-to treat RA. If this is the case, then a disturbed cortisol circadian rhythm reflecting this impairment may serve as a predictor of difficult-to-treat RA during the first diagnosis. In order to address this issue, the investigators designed a prospective cohort study including adult patients with Rheumatoid arthritis who require drug treatment for the first time or escalation of existing treatment due to active disease. Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens when started will not exceed 15 mg/day, and will be given for at least 3 months), following EULAR recommendations for RA treatment.
Patients will be monitored at baseline, 3 months, 6 months and 12 months, assessing disease response to treatment, the need for continuing glucocorticoid treatment, inflammatory indexes, and diurnal salivary cortisol levels. Patients' classification will be based on EULAR response to treatment criteria for RA and cortisol circadian rhythm will be comparatively assessed (at baseline and at 3/6/12 months) between groups based on treatment response (EULAR guidelines).
Read the detailed description
It is well known that a proportion of patients with RA is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs (DMARDs).The European League Against Rheumatism (EULAR), acknowledging the critical issue of the GCs-induced complications, suggested in the most recent update of the RA management guidelines tapering (on sustained clinical remission) of oral GCs treatment at the earliest feasible time point of therapeutic course and to the lowest daily dose, preferably <7.5mg/day (prednisone equivalent), until the final target of withdrawal is succeeded. In clinical practice, these guidelines are often difficult to follow. In any case, the inability of tapering oral GC below 7.5mg/day of prednisone or an equivalent synthetic GC is included in the recent definition of difficult-to-treat RA.
Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in RA. Although the underlying molecular mechanisms are unknown, both chronic overexpression of proinflammatory cytokines and chronic stress may contribute the most in the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis and the target tissue glucocorticoid resistance that have been described, but not systematically studied. Thus, a precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management.
Recently the investigators have assessed the cortisol circadian rhythm, using saliva measurements, in patients with acute viral infection, as is COVID-19, comparing to healthy controls. In this study COVID-19 patients had almost 6-fold higher mean serum CRP and IL-6 levels than controls (p<0.001), whereas morning salivary cortisol levels were similar in the two groups. Diurnal cortisol rhythm in these patients was blunted, with increased evening and nocturnal levels, resulting in higher time-integrated daily cortisol secretion in patients than controls (area under the curve: 4.81±2.46 vs.2.75±0.810, respectively, p<0.001).
Based on the above, the investigators will test the hypothesis that an impaired functional reserve of adrenal cortex, due to chronic over-expression of pro-inflammatory cytokines and/or chronic stress may contribute to RA development and/or associate with difficult-to treat RA. If this is the case, then a disturbed cortisol circadian rhythm reflecting this impairment may serve as a predictor of difficult-to-treat RA.
In order to address this issue, the investigators designed the following study, considering the fact that the tested hypothesis seems to be a JANUS hypothesis since those patients who are at need of corticosteroids to maintain low disease activity or remission could have either high or low evening/night cortisol levels at baseline.
Study Design
This is a single-center prospective cohort study of 50 consecutive RA adult patients (fulfilling the 2010 ACR/EULAR classification criteria) who are:
- newly -diagnosed and are going to start treatment, or
- require escalation of drug treatment due to active disease (addition of biologic or cDMARD or change of biologic with or without corticosteroids) providing that are off corticosteroid treatment for at least 3 months.
Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment.
Time points of assessment:
Baseline (day 0), months 3, months 6 and 12 months. Blood samples, diurnal salivary cortisol samples and questionnaires regarding self-perceived stress and Hamilton scale for depression will be collected from all recruited individuals. Important NOTE: those who are on corticosteroids at 3 and/or 6 months (preferably below 7.5mg of prezolon) will be advised to stop corticosteroids treatment for 48 h before saliva measurements.
Patients' classification will be based on EULAR response to treatment criteria for RA at month 3 and month 6 and 12 months compared to baseline (moderate and good response patients may be considered together).
Patients will be recruited from the Outpatient clinic for Rheumatology and autoimmune diseases of Medical School, National and Kapodistrian University of Athens located at LAIKO University Hospital, 17 Agiou Thoma, 11527, Athens, Greece.
Cortisol circadian rhythm will be comparatively assessed (at baseline and at 3/6/12 months) between responders Vs non-responders and a post-hoc analysis will be performed on the longitudinal changes in the cortisol circadian rhythm in relation to the clinical status and stress/depression levels of the individual patients.
Age- and sex-matched apparently healthy volunteers who fulfill the inclusion/exclusion criteria will be recruited from the Hospital personnel during the same time-period and serve as controls, in a case -control, cross-sectional analysis to investigate differences between circadian cortisol rhythm between patients and healthy individuals.
All participants will sign an informed consent and the procedures followed will be in accordance with the 1975/83 Declaration of Helsinki. The study is approved by the scientific committee of Laikon Athens University-Hospital (Approval number E.Σ. 38/21-01-2021).
- Conditions
- Rheumatoid Arthritis
- Being tested
- DMARDs
- Keywords
- salivary cortisol, hypothalamus-pituitary-adrenal axis, circadian rhythm, adrenals, response to treatment
- Medical subject headings
- Arthritis, Rheumatoid
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DMARDsDrug
Also called Corticosteroid regimens that do not exceed 15 mg/day
Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment.
| Study group | Role | What they receive |
|---|---|---|
| patients with Rheumatoid arthritis and good response at 3/6/12 months | Patients with Rheumatoid arthritis that fulfill the inclusion/exclusion criteria and show a good response at 3/6 or 12 months upon recruitment according to EULAR guidelines with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day) Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment. Receives: Drug: DMARDs | |
| patients with Rheumatoid arthritis and none at 3/6/12 months | Patients with Rheumatoid arthritis that fulfill the inclusion/exclusion criteria and show none response at 3/6 or 12 months upon recruitment according to EULAR guidelines.
Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment. Receives: Drug: DMARDs |
What is being measured
The primary outcome is the main question the study is designed to answer.
Circadian Rhythm of cortisol
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Measured: Salivary samples will be obtained at prescheduled timepoints, 8am, for measurement of free cortisol levels.
Circadian Rhythm of cortisol
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Measured: Salivary samples will be obtained at 12-noon for measurements of free cortisol levels.
Circadian Rhythm of cortisol
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Measured: Salivary samples will be obtained at 6pm for measurements of free cortisol levels.
Circadian Rhythm of cortisol
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Measured: Salivary samples will be obtained at 10pm for measurements of free cortisol levels.
Secondary outcomes (7)
Serum DHEAS levels
Measurement of DHEAS levels (Immulite 2000 Siemen)
Measured: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Serum DHEAS levels
Measurement of DHEAS levels (Immulite 2000 Siemen)
Measured: Blood samples will be obtained from patients at 3 months of treatment during morning hours after overnight fast
Serum DHEAS levels
Measurement of DHEAS levels (Immulite 2000 Siemen)
Measured: Blood samples will be obtained from patients at 6 months of treatment during morning hours after overnight fast
Serum DHEAS levels
Measurement of DHEAS levels (Immulite 2000 Siemen)
Measured: Blood samples will be obtained from patients at 12 months of treatment during morning hours after overnight fast
Plasma ACTH levels
Measurement of morning plasma ACTH levels sing solid-phase, two-site chemiluminescence immunoassays on an IMMULITE 2000 Immunoassay System (Siemens Healthcare Diagnostics Products Ltd, UK). ). The analytical sensitivity for ACTH measurement is 5 pg/mL . . The intra and inter- assay coefficients of variation (CV) for ACTH ranges from 6.7 to 9.5 % and from 6.1 to 10 %, respectively
Measured: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Serum CRP levels
Serum high sensitivity CRP (hsCRP) will be measured using solid-phase, two-site chemiluminescence immunoassays on an IMMULITE 2000 Immunoassay System (Siemens Healthcare Diagnostics Products Ltd, UK). The analytical sensitivity for hsCRP measurement is 0.1 mg/L. The intra and inter- assay coefficients of variation (CV) for hsCRP from 2.8 to 8.7 % and from 3.1 to 8.7 %, respectively, depending on the sample concentration.
Measured: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Serum IL-6 levels
Measurement of IL-6 levels was detected by a sandwich enzyme immunoassay using Quantikine ELISA kit (R\&D Systems, Minneapolis, MN, USA). The lower detection limit of DIAsource aldosterone assay is 15 pg/mL and the intra- and inter- assay CV lays between 4.5 and 8.7 %, respectively, depending on sample concentration. The lower detectable measurement of IL-6 is 0.70 pg/mL and the inter- and intra- assay precision ranged between 1.6 and 4.2 and from 3.3 to 6.4, respectively.
Measured: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted4 Jan 2023
- Study start2 Feb 2022
- Primary completion30 May 2023 (estimated)
- Study completion30 Jun 2023 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (7)Papers the sponsor has linked to this study.
- Other trials for Rheumatoid ArthritisStudies of the same condition, open and under way.
- More trials run by National and Kapodistrian University of AthensThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 50 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National and Kapodistrian University of Athens
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Maria Yavropoulou, National and Kapodistrian University of Athens
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05671627
- Sponsor's protocol ID
- EΣ-38/ 21-1-2021
- Acronym
- CortRyRA
- Status last verified
- Dec 2022
- First submitted
- 19 Sep 2022
- Last updated
- 4 Jan 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Yavropoulou MP, Filippa MG, Panopoulos S, Spanos E, Spanos G, Tektonidou MG, Sfikakis PP. Impaired adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases who relapse upon tapering of low glucocorticoid dose. Clin Exp Rheumatol. 2022 Sep;40(9):1789-1792. doi: 10.55563/clinexprheumatol/x78tko. Epub 2022 Jun 13.
PubMed 35699085Tan Y, Buch MH. 'Difficult to treat' rheumatoid arthritis: current position and considerations for next steps. RMD Open. 2022 Jul;8(2):e002387. doi: 10.1136/rmdopen-2022-002387.
PubMed 35896282Burmester GR, Buttgereit F, Bernasconi C, Alvaro-Gracia JM, Castro N, Dougados M, Gabay C, van Laar JM, Nebesky JM, Pethoe-Schramm A, Salvarani C, Donath MY, John MR; SEMIRA collaborators. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276. doi: 10.1016/S0140-6736(20)30636-X.
PubMed 32711802Yavropoulou MP, Filippa MG, Mantzou A, Ntziora F, Mylona M, Tektonidou MG, Vlachogiannis NI, Paraskevis D, Kaltsas GA, Chrousos GP, Sfikakis PP. Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations. Endocrine. 2022 Feb;75(2):317-327. doi: 10.1007/s12020-021-02968-8. Epub 2022 Jan 18.
PubMed 35043384Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, Gorter S, Knevel R, Nam J, Schoels M, Aletaha D, Buch M, Gossec L, Huizinga T, Bijlsma JW, Burmester G, Combe B, Cutolo M, Gabay C, Gomez-Reino J, Kouloumas M, Kvien TK, Martin-Mola E, McInnes I, Pavelka K, van Riel P, Scholte M, Scott DL, Sokka T, Valesini G, van Vollenhoven R, Winthrop KL, Wong J, Zink A, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010 Jun;69(6):964-75. doi: 10.1136/ard.2009.126532. Epub 2010 May 5.
PubMed 20444750Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Rheum Dis Clin North Am. 2009 Nov;35(4):745-57, vii-viii. doi: 10.1016/j.rdc.2009.10.001.
PubMed 19962619Yavropoulou MP, Filippa MG, Vlachogiannis NI, Fragoulis GE, Laskari K, Mantzou A, Panopoulos S, Fanouriakis A, Bournia VK, Evangelatos G, Papapanagiotou A, Tektonidou MG, Chrousos GP, Sfikakis PP. Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study. RMD Open. 2024 Jan 17;10(1):e003575. doi: 10.1136/rmdopen-2023-003575.
PubMed 38233075
Study at a glance
From the registry record, last updated by the sponsor on 4 Jan 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Impaired Functional Reserve of Adrenal Cortex May Associate With difficult-to Treat RA: Can a Disturbed Cortisol Circadian Rhythm Serve as a Predictor of Difficult-to-treat RA?
- ClinicalTrials.gov ID
- NCT05671627
- Acronym / sponsor ID
- CortRyRA / EΣ-38/ 21-1-2021
- Conditions
- Rheumatoid Arthritis
- Keywords
- salivary cortisol, hypothalamus-pituitary-adrenal axis, circadian rhythm, adrenals, response to treatment
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 50 participants (estimated)
- Lead sponsor
- National and Kapodistrian University of AthensUniversity, hospital or other
- Study start
- 2 Feb 2022 (actual)
- Primary completion
- 30 May 2023 (estimated)
- Study completion
- 30 Jun 2023 (estimated)
- First posted
- 4 Jan 2023 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The European League Against Rheumatism (EULAR), acknowledging the critical issue of the complications, of long term treatment with glucocorticoids in the most recent update of the management guidelines for Rheumatoid arthritis, recommends tapering (on sustained clinical remission) of oral glucocorticoids treatment at the earliest feasible time point of therapeutic course and to the lowest daily dose, preferably <7.5mg/day (prednisone equivalent), until the final target of withdrawal is succeeded. In clinical practice, these guidelines are often difficult to follow due to the high risk of disease flares after tapering or stopping glucocorticoids administration. This inability of tapering oral glucocorticoids below 7.5mg/day of prednisone or an equivalent synthetic glucocorticoid is included in the recent definition of difficult-to-treat Rheumatoid arthritis. SΕΜΙRΑ (Steroid EliMination In Rheumatoid Arthritis) study, a double-blind, multicentre, randomised controlled trial, compared oral glucocorticoids tapering with the continuation of low dose oral glucocorticoids. The population study consisted of 259 RA patients with low disease activity on treatment with 5mg per day prednisone and tocilizumab, an anti-interleukin (IL)-6 receptor antibody. The study demonstrated that the continued-prednisone regimen provided better maintenance of disease remission than did the tapered-prednisone regimen for the study period of 24 weeks with no symptoms suggestive of AI. However, the study protocol did not include biochemical assessment of adrenocortical function.
Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in Rheumatoid arthritis. Although the underlying molecular mechanisms remain unknown, both chronic overexpression of proinflammatory cytokines and chronic stress may contribute in the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis and the target tissue glucocorticoid resistance that have been described, but not systematically studied. Thus, a precise longitudinal assessment of endogenous cortisol production may be needed for optimal management of patients with Rheumatoid arthritis. Based on the above, the investigators seek to investigate the hypothesis that an impaired functional reserve of adrenal cortex, due to chronic over-expression of pro-inflammatory cytokines and/or chronic stress may contribute to the development of Rheumatoid arthritis and/or associate with difficult-to treat RA. If this is the case, then a disturbed cortisol circadian rhythm reflecting this impairment may serve as a predictor of difficult-to-treat RA during the first diagnosis. In order to address this issue, the investigators designed a prospective cohort study including adult patients with Rheumatoid arthritis who require drug treatment for the first time or escalation of existing treatment due to active disease. Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens when started will not exceed 15 mg/day, and will be given for at least 3 months), following EULAR recommendations for RA treatment.
Patients will be monitored at baseline, 3 months, 6 months and 12 months, assessing disease response to treatment, the need for continuing glucocorticoid treatment, inflammatory indexes, and diurnal salivary cortisol levels. Patients' classification will be based on EULAR response to treatment criteria for RA and cortisol circadian rhythm will be comparatively assessed (at baseline and at 3/6/12 months) between groups based on treatment response (EULAR guidelines).
Detailed description
It is well known that a proportion of patients with RA is always in need of even small doses of glucocorticoids to maintain clinical remission, despite concomitant treatment with conventional and biologic disease-modifying drugs (DMARDs).The European League Against Rheumatism (EULAR), acknowledging the critical issue of the GCs-induced complications, suggested in the most recent update of the RA management guidelines tapering (on sustained clinical remission) of oral GCs treatment at the earliest feasible time point of therapeutic course and to the lowest daily dose, preferably <7.5mg/day (prednisone equivalent), until the final target of withdrawal is succeeded. In clinical practice, these guidelines are often difficult to follow. In any case, the inability of tapering oral GC below 7.5mg/day of prednisone or an equivalent synthetic GC is included in the recent definition of difficult-to-treat RA.
Experimental and clinical data have suggested that inadequate production of endogenous cortisol relative to enhanced clinical needs associated with the systemic inflammatory response, coined as the 'disproportion principle', may operate in RA. Although the underlying molecular mechanisms are unknown, both chronic overexpression of proinflammatory cytokines and chronic stress may contribute the most in the hyporesponsiveness of the hypothalamic-pituitary-adrenal axis and the target tissue glucocorticoid resistance that have been described, but not systematically studied. Thus, a precise longitudinal assessment of endogenous cortisol production may be needed for optimal RA management.
Recently the investigators have assessed the cortisol circadian rhythm, using saliva measurements, in patients with acute viral infection, as is COVID-19, comparing to healthy controls. In this study COVID-19 patients had almost 6-fold higher mean serum CRP and IL-6 levels than controls (p<0.001), whereas morning salivary cortisol levels were similar in the two groups. Diurnal cortisol rhythm in these patients was blunted, with increased evening and nocturnal levels, resulting in higher time-integrated daily cortisol secretion in patients than controls (area under the curve: 4.81±2.46 vs.2.75±0.810, respectively, p<0.001).
Based on the above, the investigators will test the hypothesis that an impaired functional reserve of adrenal cortex, due to chronic over-expression of pro-inflammatory cytokines and/or chronic stress may contribute to RA development and/or associate with difficult-to treat RA. If this is the case, then a disturbed cortisol circadian rhythm reflecting this impairment may serve as a predictor of difficult-to-treat RA.
In order to address this issue, the investigators designed the following study, considering the fact that the tested hypothesis seems to be a JANUS hypothesis since those patients who are at need of corticosteroids to maintain low disease activity or remission could have either high or low evening/night cortisol levels at baseline.
Study Design
This is a single-center prospective cohort study of 50 consecutive RA adult patients (fulfilling the 2010 ACR/EULAR classification criteria) who are:
- newly -diagnosed and are going to start treatment, or
- require escalation of drug treatment due to active disease (addition of biologic or cDMARD or change of biologic with or without corticosteroids) providing that are off corticosteroid treatment for at least 3 months.
Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment.
Time points of assessment:
Baseline (day 0), months 3, months 6 and 12 months. Blood samples, diurnal salivary cortisol samples and questionnaires regarding self-perceived stress and Hamilton scale for depression will be collected from all recruited individuals. Important NOTE: those who are on corticosteroids at 3 and/or 6 months (preferably below 7.5mg of prezolon) will be advised to stop corticosteroids treatment for 48 h before saliva measurements.
Patients' classification will be based on EULAR response to treatment criteria for RA at month 3 and month 6 and 12 months compared to baseline (moderate and good response patients may be considered together).
Patients will be recruited from the Outpatient clinic for Rheumatology and autoimmune diseases of Medical School, National and Kapodistrian University of Athens located at LAIKO University Hospital, 17 Agiou Thoma, 11527, Athens, Greece.
Cortisol circadian rhythm will be comparatively assessed (at baseline and at 3/6/12 months) between responders Vs non-responders and a post-hoc analysis will be performed on the longitudinal changes in the cortisol circadian rhythm in relation to the clinical status and stress/depression levels of the individual patients.
Age- and sex-matched apparently healthy volunteers who fulfill the inclusion/exclusion criteria will be recruited from the Hospital personnel during the same time-period and serve as controls, in a case -control, cross-sectional analysis to investigate differences between circadian cortisol rhythm between patients and healthy individuals.
All participants will sign an informed consent and the procedures followed will be in accordance with the 1975/83 Declaration of Helsinki. The study is approved by the scientific committee of Laikon Athens University-Hospital (Approval number E.Σ. 38/21-01-2021).
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| patients with Rheumatoid arthritis and good response at 3/6/12 months | – | Drug: DMARDsPatients with Rheumatoid arthritis that fulfill the inclusion/exclusion criteria and show a good response at 3/6 or 12 months upon recruitment according to EULAR guidelines with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day) Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment. |
| patients with Rheumatoid arthritis and none at 3/6/12 months | – | Drug: DMARDsPatients with Rheumatoid arthritis that fulfill the inclusion/exclusion criteria and show none response at 3/6 or 12 months upon recruitment according to EULAR guidelines. Patients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment. |
Who may qualify
- Ages
- 20 to 80 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- All consecutive adult patients fulfilling the 2010 ACR/EULAR classification criteria that visit the Outpatient clinic for Rheumatology and autoimmune diseases.
Key inclusion criteria (3 listed)
- Newly -diagnosed and are going to start treatment, or
- require escalation of drug treatment due to active disease (addition of biologic or cDMARD or change of biologic with or without corticosteroids) providing that are off corticosteroid treatment for at least 6 months.
Key exclusion criteria (9 listed)
- chronic kidney disease stage 3b and above,
- antineoplastic treatment,
- TSH>10 IU/lt,
- Cushing syndrome
- hypo-/hyper-parathyroidism
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DMARDsAlso: Corticosteroid regimens that do not exceed 15 mg/dayPatients will be treated as per clinician's judgement with any kind or combination of DMARDs with or without corticosteroids (corticosteroid regimens do not exceed 15 mg/day), following EULAR recommendations for RA treatment. | Drug | patients with Rheumatoid arthritis and good response at 3/6/12 months, patients with Rheumatoid arthritis and none at 3/6/12 months |
Primary outcome
Circadian Rhythm of cortisol
Time frame: Salivary samples will be obtained at prescheduled timepoints, 8am, for measurement of free cortisol levels.
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Circadian Rhythm of cortisol
Time frame: Salivary samples will be obtained at 12-noon for measurements of free cortisol levels.
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Circadian Rhythm of cortisol
Time frame: Salivary samples will be obtained at 6pm for measurements of free cortisol levels.
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
Circadian Rhythm of cortisol
Time frame: Salivary samples will be obtained at 10pm for measurements of free cortisol levels.
Salivary samples for cortisol measurements will be collected using the Salivette device (Sarstedt, Nümbrecht, Germany). The participants will be asked to refrain from eating and brushing their teeth for 1 hour before the collection. The measurements will be performed by an electrochemiluminescence immunoassay on the automated analyzer Cobas e411-Roche Diagnostics (GmbH, Mannheim). The detection limit is 0.054 mcg/dL and the intra- and inter-assay CV is 6.1% and 11.8%, respectively, at the concentration of 0.137 mcg/dL.
7 secondary outcomes
Serum DHEAS levels
Time frame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Serum DHEAS levels
Time frame: Blood samples will be obtained from patients at 3 months of treatment during morning hours after overnight fast
Serum DHEAS levels
Time frame: Blood samples will be obtained from patients at 6 months of treatment during morning hours after overnight fast
Serum DHEAS levels
Time frame: Blood samples will be obtained from patients at 12 months of treatment during morning hours after overnight fast
Plasma ACTH levels
Time frame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Serum CRP levels
Time frame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Serum IL-6 levels
Time frame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 4 Jan 2023.
- Background: PubMed 35699085Yavropoulou MP, Filippa MG, Panopoulos S, Spanos E, Spanos G, Tektonidou MG, Sfikakis PP. Impaired adrenal cortex reserve in patients with rheumatic and musculoskeletal diseases who relapse upon tapering of low glucocorticoid dose. Clin Exp Rheumatol. 2022 Sep;40(9):1789-1792. doi: 10.55563/clinexprheumatol/x78tko. Epub 2022 Jun 13.
- Background: PubMed 35896282Tan Y, Buch MH. 'Difficult to treat' rheumatoid arthritis: current position and considerations for next steps. RMD Open. 2022 Jul;8(2):e002387. doi: 10.1136/rmdopen-2022-002387.
- Background: PubMed 32711802Burmester GR, Buttgereit F, Bernasconi C, Alvaro-Gracia JM, Castro N, Dougados M, Gabay C, van Laar JM, Nebesky JM, Pethoe-Schramm A, Salvarani C, Donath MY, John MR; SEMIRA collaborators. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276. doi: 10.1016/S0140-6736(20)30636-X.
- Background: PubMed 35043384Yavropoulou MP, Filippa MG, Mantzou A, Ntziora F, Mylona M, Tektonidou MG, Vlachogiannis NI, Paraskevis D, Kaltsas GA, Chrousos GP, Sfikakis PP. Alterations in cortisol and interleukin-6 secretion in patients with COVID-19 suggestive of neuroendocrine-immune adaptations. Endocrine. 2022 Feb;75(2):317-327. doi: 10.1007/s12020-021-02968-8. Epub 2022 Jan 18.
- Background: PubMed 20444750Smolen JS, Landewe R, Breedveld FC, Dougados M, Emery P, Gaujoux-Viala C, Gorter S, Knevel R, Nam J, Schoels M, Aletaha D, Buch M, Gossec L, Huizinga T, Bijlsma JW, Burmester G, Combe B, Cutolo M, Gabay C, Gomez-Reino J, Kouloumas M, Kvien TK, Martin-Mola E, McInnes I, Pavelka K, van Riel P, Scholte M, Scott DL, Sokka T, Valesini G, van Vollenhoven R, Winthrop KL, Wong J, Zink A, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010 Jun;69(6):964-75. doi: 10.1136/ard.2009.126532. Epub 2010 May 5.
- Background: PubMed 19962619Fransen J, van Riel PL. The Disease Activity Score and the EULAR response criteria. Rheum Dis Clin North Am. 2009 Nov;35(4):745-57, vii-viii. doi: 10.1016/j.rdc.2009.10.001.
- Derived from this study: PubMed 38233075Yavropoulou MP, Filippa MG, Vlachogiannis NI, Fragoulis GE, Laskari K, Mantzou A, Panopoulos S, Fanouriakis A, Bournia VK, Evangelatos G, Papapanagiotou A, Tektonidou MG, Chrousos GP, Sfikakis PP. Diurnal production of cortisol and prediction of treatment response in rheumatoid arthritis: a 6-month, real-life prospective cohort study. RMD Open. 2024 Jan 17;10(1):e003575. doi: 10.1136/rmdopen-2023-003575.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Rheumatoid Arthritis, run by National and Kapodistrian University of Athens at 1 site in Greece.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 9 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 4 Jan 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Maria Yavropoulou, M.D. (00306936159517, myavropoulou@med.uoa.gr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Circadian Rhythm of cortisol (time frame: Salivary samples will be obtained at prescheduled timepoints, 8am, for measurement of free cortisol levels.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05671627, which also lists 7 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 4 Jan 2023.