Cortisol Circadian Rhythm in Patients With RA

NCT05671627 | Unknown

• 1 other identifier: EΣ-38/ 21-1-2021
• Study Type: observational
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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 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).

Conditions

Rheumatoid Arthritis

Keywords

salivary cortisol; hypothalamus-pituitary-adrenal axis; circadian rhythm; adrenals; response to treatment

Outcome Measures

Primary Outcomes (4)

• 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.

  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.

  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.

  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.

  Salivary samples will be obtained at 10pm for measurements of free cortisol levels.

Secondary Outcomes (7)

• Serum DHEAS levels

  Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast

• Serum DHEAS levels

  Blood samples will be obtained from patients at 3 months of treatment during morning hours after overnight fast

• Serum DHEAS levels

  Blood samples will be obtained from patients at 6 months of treatment during morning hours after overnight fast

• Serum DHEAS levels

  Blood samples will be obtained from patients at 12 months of treatment during morning hours after overnight fast

• Plasma ACTH levels

  Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast

Study Arms (2)

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.

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.

Drug: DMARDs

Interventions

DMARDs DRUG

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.

Also known as: Corticosteroid regimens that do not exceed 15 mg/day

patients with Rheumatoid arthritis and good response at 3/6/12 months; patients with Rheumatoid arthritis and none at 3/6/12 months

Eligibility Criteria

• Age: 20 Years - 80 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

All consecutive adult patients fulfilling the 2010 ACR/EULAR classification criteria that visit the Outpatient clinic for Rheumatology and autoimmune diseases.

You may qualify if:

• 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.

You may not qualify if:

• chronic kidney disease stage 3b and above,
• antineoplastic treatment,
• TSH\>10 IU/lt,
• Cushing syndrome
• hypo-/hyper-parathyroidism
• estrogen replacement therapy
• insulin treatment or HBA1c\>7.5 %,
• BMI\>35
• pregnancy

Sponsors & Collaborators

• National and Kapodistrian University of Athens: lead

Study Sites (1)

Laiko General Hospital

Athens, 11527, Greece

RECRUITING

Related Publications (7)

• 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.

  PMID: 35699085 BACKGROUND

• Tan 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.

  PMID: 35896282 BACKGROUND

• Burmester 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.

  PMID: 32711802 BACKGROUND

• Yavropoulou 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.

  PMID: 35043384 BACKGROUND

• Smolen 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.

  PMID: 20444750 BACKGROUND

• Fransen 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.

  PMID: 19962619 BACKGROUND

• Yavropoulou 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.

  PMID: 38233075 DERIVED

Biospecimen

Retention: SAMPLES WITHOUT DNA

Blood and saliva

MeSH Terms

Conditions

Arthritis, Rheumatoid

Interventions

Antirheumatic Agents

Condition Hierarchy (Ancestors)

Arthritis; Joint Diseases; Musculoskeletal Diseases; Rheumatic Diseases; Connective Tissue Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Therapeutic Uses; Pharmacologic Actions; Chemical Actions and Uses

Central Study Contacts

Maria Yavropoulou, M.D.

CONTACT

00306936159517; myavropoulou@med.uoa.gr

Petros Sfikakis, M.D.

CONTACT

00306936233816; psfikakis@med.uoa.gr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal investigator

Study Record Dates

• First Submitted: September 19, 2022
• First Posted: January 4, 2023
• Study Start: February 2, 2022
• Primary Completion: May 30, 2023
• Study Completion: June 30, 2023
• Last Updated: January 4, 2023

Record last verified: 2022-12

Locations

GR (1)