Clinical trial NCT05671627: Cortisol Circadian Rhythm in Patients With RA
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?
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Rheumatoid Arthritis
Keywords: salivary cortisol
hypothalamus-pituitary-adrenal axis
circadian rhythm
adrenals
response to treatment
Lead sponsor: National and Kapodistrian University of Athens
Sponsor class: OTHER
First posted: 2023-01-04
Enrollment: 50
Sex: ALL
Minimum age (years): 20
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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).

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:

1. newly -diagnosed and are going to start treatment, or
2. 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).

Eligibility criteria: Inclusion Criteria:

RA adult patients (fulfilling the 2010 ACR/EULAR classification criteria) who are:

1. Newly -diagnosed and are going to start treatment, or
2. 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.

Exclusion Criteria:

* 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

Primary outcomes:
measure: Circadian Rhythm of cortisol
timeFrame: Salivary samples will be obtained at prescheduled timepoints, 8am, for measurement of free cortisol levels.
measure: Circadian Rhythm of cortisol
timeFrame: Salivary samples will be obtained at 12-noon for measurements of free cortisol levels.
measure: Circadian Rhythm of cortisol
timeFrame: Salivary samples will be obtained at 6pm for measurements of free cortisol levels.
measure: Circadian Rhythm of cortisol
timeFrame: Salivary samples will be obtained at 10pm for measurements of free cortisol levels.
Secondary outcomes:
measure: Serum DHEAS levels
timeFrame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
measure: Serum DHEAS levels
timeFrame: Blood samples will be obtained from patients at 3 months of treatment during morning hours after overnight fast
measure: Serum DHEAS levels
timeFrame: Blood samples will be obtained from patients at 6 months of treatment during morning hours after overnight fast
measure: Serum DHEAS levels
timeFrame: Blood samples will be obtained from patients at 12 months of treatment during morning hours after overnight fast
measure: Plasma ACTH levels
timeFrame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
measure: Serum CRP levels
timeFrame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
measure: Serum IL-6 levels
timeFrame: Blood samples will be obtained from patients and controls immediately upon recruitment at morning hours after overnight fast
Other outcomes:
Locations:
city: Athens
country: Greece
facility: Laiko General Hospital
Study officials:
References:
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citation: 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.
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