Adrenocorticotropic hormone response to hypoglycemic stress was preserved by a single bedtime 3-mg dose of prednisolone in patients with rheumatoid arthritis

We have studied the effect of low-dose prednisolone administered before sleep on the hypothalamic–pituitary–adrenal axis and the symptoms of patients with rheumatoid arthritis (RA). Plasma adrenocorticotropic hormone (ACTH) and serum cortisol levels were measured in the basal state and after hypoglycemic stress induced by the insulin tolerance test in 21 patients receiving prednisolone at 3–5 mg daily. The patient's global assessment of their disease activity scores on a 100-mm visual analogue scale (VAS) and self-reporting of their functional status using the health assessment questionnaire (HAQ) were evaluated. While both the cortisol and the ACTH responses were impaired dose-dependently in patients treated with prednisolone, the ACTH response was maintained in patients treated with a single daily 3-mg dose of prednisolone before sleep. There was an inverse correlation between the extent of the ACTH response and disease activity as revealed by the VAS (r = 0.521, P < 0.05). There was also a weak correlation between VAS and the self-rating depression scale (SDS) (r = 0.443), especially when only patients with an HAQ score > 10 were included in order to exclude any possible contribution of the limitations in the activities of daily living to the SDS score (r = 0.859, P < 0.05). These results suggest that a single daily low dose (3 mg) of prednisolone administered before sleep maintains the ACTH response in RA patients, and patients with a good ACTH response appear to be less depressed and have milder symptoms.     

Reliability,validity and responsiveness of a new leisure index: The Patient‐Specific Leisure Scale (PSLS)

Objectives: To investigate the reliability, validity and responsiveness of a new Patient‐Specific Leisure Scale (PSLS), constructed to identify goals and outcomes for individual patients with rheumatoid arthritis (RA). Methods: Forty‐nine patients with RA were used to evaluate test–retest reliability, and 100 consecutive RA patients were used for construct validity. Twenty‐five RA patients, commencing with treatment on tumour necrosis factor (TNF) inhibitors, were evaluated before the start and after three months of therapy, to test responsiveness. The most important leisure activity (as judged by the patients) was used when evaluating reliability and validity. The perceived difficulty with each activity was scored from 0 to 10 (0 = able to perform activity without difficulty, 10 = unable to perform activity). Results: Test–retest reliability indicated a good agreement (0.62–0.87) using weighted kappa. Construct validity was demonstrated by modest positive correlation between leisure activity and Health Assessment Questionnaire (HAQ) (r_s = 0.27, p = 0.005) visual a nalogue s cale (VAS) pain (r_s = 0.28, p = 0.004) VAS global (r_s = 0.22, p = 0.027), VAS fatigue (r_s = 0.24, p = 0.013), joint index of 28 swollen joints (r_s = 0.22, p = 0.027) and negative correlations with short‐form‐36 (SF‐36) physical functioning (r_s = ?0.18, p = 0.008), bodily pain (r_s = ?0.31, p < 0.001), general health (r_s = ?0.23, p = 0.019), vitality (r_s = ?0.31, p < 0.001), social function (r_s = ?0.24, p = 0.016) and role‐emotional (r_s = ?0.28, p = 0.005). Mean improvement for the most important leisure activity was 1.36, (p = 0.036, 95% confidence interval 0.10–2.62). Standardized response mean and effect size for the most important activity in PSLS was 1.05 and 0.72, respectively, and for HAQ 0.34 and 0.28, respectively. Conclusions: PSLS appears to be feasible, reliable, valid and responsive for measuring leisure activities in RA. It provides both an individual result which is useful in clinical work, and results at a group level. Copyright © 2009 John Wiley & Sons, Ltd.     

Long‐term anti–tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion

Objective

New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti‐TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti‐TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic–pituitary–adrenal (HPA) axis. This longitudinal anti‐TNF therapy study was designed to assess these effects in RA patients.

Methods

RA patients were given 5 infusions of anti‐TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin‐6 (IL‐6), adrenocorticotropic hormone (ACTH), 17‐hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients.

Results

Upon treatment with anti‐TNF, we observed a fast decrease in the levels of serum IL‐6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti‐TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long‐term anti‐TNF therapy.

Conclusion

Long‐term therapy with anti‐TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti‐TNF treatment in patients with RA.

     

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

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.     

Assessing the impact of rheumatoid arthritis on quality of life in a group of patients attending a rheumatology clinic in Sri Lanka

BackgroundRheumatoid arthritis (RA) has a worldwide distribution affecting 0.5–3% of the population. We used Stanford Health Assessment Questionnaire (HAQ) to assess the quality of life (QOL) in a sample of patients with RA. Disability assessment component of the HAQ; the HAQ-DI, assesses a patient's level of functional ability and has been validated and used in clinical trials extensively.ObjectiveTo find the impact of illness on quality of life, in a sample of patients with RA using HAQ, and to calculate the HAQ-DI. Additionally, to find the age distribution and relationship of HAQ-DI with VAS, DAS28 and duration of illness.MethodologyA self administered questionnaire was used in a random sample of 100 patients attending a rheumatology clinic. Statistical analysis was done using the SPSS statistical package version 17 (SPSS Institute, Chicago).ResultsWe had a 100% female population with mild disease [HAQ-DI (0–<1)] in 62% of patients, while severe disease (≥2 and ≤3) was found in 5%. RA prevalence was highest in 41–50 years group (mean age ± SD = 50.8 ± 11.5 years). VAS had a positive correlation with HAQ-DI. Relationship of HAQ-DI and DAS28 was not statistically significant (p = 0.72), although there was a positive correlation between DAS28 and HAQ-DI in disease duration more than 5 years group (r = 0.19). Mean HAQ score was the highest in more than 10 years disease duration population (p = 0.006).ConclusionIn a busy clinic setting, simple parameters like disease duration and VAS give an indication about the functional effect of illness on a patient's quality of life.     

Adrenocorticotropic hormone and dehydroepiandrosterone sulfate levels of rheumatoid arthritis patients treated with glucocorticoids

Abstract

To assess adrenal function with respect to the presence or absence of steroid therapy, we investigated differences in the blood levels of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) in relation to steroid (prednisolone) administration in 123 patients with rheumatoid arthritis (RA). Levels of ACTH and DHEAS were significantly lower in the steroid-treated group than in the non-treated group (ACTH: 11.79?pg/ml vs 27.92?pg/ml) (DHEAS: 418.12?ng/ml vs 883.91?ng/ml) (P < 0.0001). We observed no steroid dose-related differences in ACTH levels. However, DHEAS levels showed a slight decrease at a prednisolone dose of 2.5?mg/day, with a significant decrease being observed at a dose of 5?mg/day when statistical adjustments were made for age and sex (P < 0.0001). At doses of 7.5?mg/day or greater, DHEAS levels were significantly lower than those for 5?mg/day (P < 0.0006). These results suggest that low-dose prednisolone reduces adrenal function in patients with RA. We recommend that doses of prednisolone should be limited to 5?mg/day or less in consideration of adrenal function when treating RA patients. The measurement of ACTH and DHEAS may be useful for evaluating adrenal function in patients with RA.     

The effect of therapeutic glucocorticoids on the adrenal response in a randomized controlled trial in patients with rheumatoid arthritis

OBJECTIVE: To measure the effect of low-dose systemic glucocorticoid treatment on the adrenal response to adrenocorticotropic hormone (ACTH) in patients with rheumatoid arthritis (RA). METHODS: Patients with RA who took part in a randomized double-blind placebo-controlled trial of budesonide (3 mg/day and 9 mg/day) and prednisolone (7.5 mg/day) underwent a short (60-minute) test with injection of ACTH (tetracosactide hexaacetate) at baseline and the day after completing the 3-month treatment program. Plasma cortisol measurements at baseline and 3 months were compared within and between the treatment groups. Individual patients were classified as normal responders to ACTH or as abnormal responders if changes were >2 SD below the pretreatment value in the entire group of study patients. RESULTS: Short tests with ACTH injection were performed on 139 patients before beginning the study medication and on 134 patients after cessation of the medication. There were no changes in the placebo group. Mean plasma cortisol levels following treatment were reduced in all active treatment groups. In addition, mean values were significantly reduced for the 30-minute and 60-minute responses to ACTH. The maximum reduction (35%) occurred in the prednisolone group at 60 minutes. Following treatment, 34% of patients taking budesonide 9 mg and 46% of those taking prednisolone 7.5 mg failed to reach the normal maximum cortisol response to ACTH. Four patients failed to achieve the normal percentage increase in cortisol levels, but only 1 patient failed to meet both criteria. CONCLUSION: Low doses of a glucocorticoid resulted in depression of baseline and ACTH-stimulated cortisol levels after 12 weeks of therapy. Although the responsiveness of the hypothalamic-pituitary-adrenal axis in individual patients generally remained within the normal range, these changes should be investigated further.     

The effects of alcoholism on the hypothalamic-pituitary-adrenal axis: interaction with endogenous opioid peptides

BACKGROUND Abnormal baseline hypothalamic-pituitary-adrenal axis function and dexamethasone suppressibility seen in withdrawing alcoholics returns to normal on abstinence, but some studies report blunting of the ACTH response to CRH persisting during the early abstinence phase. Reduced central levels of endogenous oplold peptides have been postulated to have an aetiological role In alcohol addiction. AIMS To evaluate hypothalamic-pituitary-adrenal axis function in a group of recently abstinent alcoholics using basal hormone data, naloxone (an oplold receptor antagonist), and ovine CRH. SUBJECTS Nine alcoholics (age 41.4±3.1 years) studied more than one week after the acute withdrawal period but within 6 weeks of cessation of drinking, and nine age and sex matched non-alcoholic controls. PROTOCOL Cortisol, ACTH, CRH and AVP levels were measured every 20 minutes for 2 hours between 0900 and 1100h. Twenty mg naloxone I.v. was administered at 1100h (0 minutes) and further samples for the above hormones were taken at 15, 30, 45, 60, 90 and 120 minutes. On a separate occasion, again at 1100h, oCRH 1μg/kg (n= 7 alcoholics, n = 6 controls) was administered, with samples for cortisol, ACTH and AVP taken at the same times. STATISTICS Results were examined by analysis of variance for repeated measures (ANOVA), while Incremental hormone response and area under the secretory curve (AUC) in alcoholics versus controls were compared by the two-tailed Student's t-test. Linear regression analysis was carried out to examine the relation between basal cortisol and hormone responses to naloxone and oCRH. RESULTS Basal hormone levels did not differ between the groups. The alcoholics had a blunted ACTH incremental response to naloxone (11.4±3.0 vs 21.1±25 pmol/l, P< 0.05) but the cortisol response was not signiflcantly different (205±51 vs 305±42 nmol/l, P= 0.15). The alcoholics also had a blunted ACTH incremental response to oCRH (28.7 ± 4.2 vs 41.2 ± 3.7 pmol/l, P= 0.052) and by ANOVA a significant main effect of group (alcoholic vs control) was seen (P < 0.02) for the ACTH response to oCRH. There was no difference between the groups in the cortisol Incremental response to oCRH. In the control subjects, a negative correlation was found between basal cortisol and the cortisol Increment (r=-0.82, P< 0.05) and ACTH Increment (r=-0.81, P = 0.052) following oCRH, while In contrast, basal cortisol correlated positively with cortisol increment (r= 0.72, P < 0.05) following naloxone. There was also a trend for basal cortisol to correlate positively with ACTH increment following naloxone In the controls (r= 0.63, P < 007). In the alcoholics, the normal negative effect of basal cortisol on the cortisol Increment after oCRH was reversed, with a positive correlation between basal cortisol and cortisol increment (r= 0.75, P= 0.05). CONCLUSIONS Recently abstinent alcoholics with normal basal HPA axis hormone levels have a blunted ACTH response to naloxone and oCRH. While reduced levels of central endogenous oplold peptides may be a factor in the blunted ACTH response to naloxone In the alcoholics, it Is proposed that the alcoholics have reduced pituitary responsiveness to CRH. This may be via a direct pituitary effect of the chronic ethanol exposure or by a reduction in hypothalamic-hypophyseal vasopressin levels.     

Adrenocorticotropic hormone and dehydroepiandrosterone sulfate levels of rheumatoid arthritis patients treated with glucocorticoids

To assess adrenal function with respect to the presence or absence of steroid therapy, we investigated differences in the blood levels of adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) in relation to steroid (prednisolone) administration in 123 patients with rheumatoid arthritis (RA). Levels of ACTH and DHEAS were significantly lower in the steroid-treated group than in the non-treated group (ACTH: 11.79 pg/ml vs 27.92 pg/ml) (DHEAS: 418.12 ng/ml vs 883.91 ng/ml) (P < 0.0001). We observed no steroid dose-related differences in ACTH levels. However, DHEAS levels showed a slight decrease at a prednisolone dose of 2.5 mg/day, with a significant decrease being observed at a dose of 5 mg/day when statistical adjustments were made for age and sex (P < 0.0001). At doses of 7.5 mg/day or greater, DHEAS levels were significantly lower than those for 5 mg/day (P < 0.0006). These results suggest that low-dose prednisolone reduces adrenal function in patients with RA. We recommend that doses of prednisolone should be limited to 5 mg/day or less in consideration of adrenal function when treating RA patients. The measurement of ACTH and DHEAS may be useful for evaluating adrenal function in patients with RA.     

Abnormal hypothalamic—pituitary—adrenal axis function in rheumatoid arthritis. Effects of nonsteroidal antiinflammatory drugs and water immersion

Objective. To investigate the effects of nonsteroidal antiinflammatory drug (NSAID) therapy and water immersion on hypothalamic—pituitary—adrenal (HPA) axis function in rheumatoid arthritis (RA). Methods. Plasma levels of adrenocorticotropic hormone (ACTH) and serum and urine levels of cortisol were compared in untreated RA patients, NSAID-treated RA patients, and healthy control subjects. Results. ACTH levels were significantly higher in untreated RA patients (mean ± SEM integrated area 11,377 ± 5,246 hours ng/liter) than in NSAID-treated RA patients (2,285 ± 388 hours ng/liter) or healthy controls (1,845 ± 35.5 hours ng/liter) (P < 0.001). Serum and urine cortisol levels were not significantly different between groups. Two-hour head-out water immersion had no effect. Conclusion. Elevated ACTH levels without hypercortisolemia occur in untreated RA. NSAID therapy alters HPA axis response, but immersion has no effect.     

Serum free cortisol as an ancillary tool in the interpretation of the low-dose 1-μg ACTH test

Objective Serum free cortisol, rather than serum total cortisol (TC), determines glucocorticoid activity in vivo, but how the considerable inter‐subject variation in ambient serum free cortisol affects the outcome of dynamic hypothalamic–pituitary–adrenal (HPA) assessment in noncritically ill subjects is unknown. Design, patients and measurements We performed the low‐dose 1‐μg ACTH test in 75 subjects referred for HPA evaluation. Serum TC was determined by a chemiluminescence method, and serum free cortisol was measured by the same method following equilibrium dialysis. In a subset of these patients, salivary cortisol was also measured. Results Mean fraction of free cortisol was 5·07 ± 4·08% (±SD; range 1·77–10·1%). Although no correlation was seen between TC and the fraction (%) of free serum cortisol, a positive correlation existed between baseline total and free cortisol (R = 0·539 P = 0·01), as well as between peak ACTH‐stimulated total and free cortisol (R = 0·619; P = 0·01). There was no correlation between baseline salivary cortisol and serum free cortisol and between peak ACTH‐stimulated salivary and serum free cortisol. Using the lowest attained peak serum free cortisol in subjects whose TC response to ACTH was normal (≥500 nm ), the minimal ‘pass’ level for normal serum free cortisol response to 1 μg ACTH was set at 25·0 nm . Five of the 19 subjects showing subnormal TC response to 1 μg ACTH had normal serum free cortisol response. Conclusions Discrepancies between the peak free and TC were noted mostly for subjects whose ACTH‐stimulated TC peaked between 440 and 580 nm . At this range, the measurement of serum free cortisol allows further refinement of the assessment of borderline responses to 1‐μg ACTH.     

Improvement of the HAQ score by infliximab treatment in patients with RA: its association with disease activity and joint destruction

Abstract

We conducted a two-year prospective study to clarify the efficacy of infliximab at improving the health assessment questionnaire (HAQ) score and associated factors in 67 patients with advanced rheumatoid arthritis (RA). All patients were scheduled to receive infliximab at a dose of 3 mg/kg at weeks 0, 2, 6 and every eight weeks thereafter through to week 102, and were fully examined at the time of each infusion. Parameters of disease activity such as the serum level of C-reactive protein (CRP), the serum level of matrix metalloproteinase-3 (MMP-3) and the 28-joint disease activity score (DAS28) were obtained, and the functional capabilities of the patients were assessed using the HAQ score. The serum CRP, the MMP-3, the DAS28(CRP) level, and the mean HAQ score decreased rapidly at two weeks after the start of infliximab treatment (CRP from 3.7 to 0.9 mg/dl, MMP-3 from 362.3 to 192.8 ng/ml, DAS28(CRP) from 5.6 to 3.7, and HAQ score from 1.5 to 0.9). Compared with the baseline values, the mean progression of the modified van der Heijde (vdH)–Sharp score after one year was 4.4 ± 5.8 (median: 3.0), and that after two years was 3.1 ± 6.9 (median: 1.0). A 93% reduction in the rate of joint destruction, as measured using the vdH–Sharp score, was estimated after infliximab therapy. Patients with less joint damage (shorter disease duration or lower vdH–Sharp score) regained more of their daily activities. The present study demonstrated the importance of activity control before the progression of irreversible factors, such as joint destruction, for maintaining the functional capacities of RA patients.     

Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion

OBJECTIVE: New insights into the role of tumor necrosis factor (TNF) in the pathogenesis of rheumatoid arthritis (RA) have expanded our understanding about the possible mechanisms by which anti-TNF antibody therapy reduces local synovial inflammation. Beyond local effects, anti-TNF treatment may modulate systemic antiinflammatory pathways such as the hypothalamic-pituitary-adrenal (HPA) axis. This longitudinal anti-TNF therapy study was designed to assess these effects in RA patients. METHODS: RA patients were given 5 infusions of anti-TNF at weeks 0, 2, 6, 10, and 14, with followup observation until week 16. We measured serum levels of interleukin-6 (IL-6), adrenocorticotropic hormone (ACTH), 17-hydroxyprogesterone (17[OH]progesterone), cortisol, cortisone, androstenedione (ASD), dehydroepiandrosterone (DHEA), and DHEA sulfate in 19 RA patients. RESULTS: Upon treatment with anti-TNF, we observed a fast decrease in the levels of serum IL-6, particularly in RA patients who did not receive parallel prednisolone treatment (P = 0.043). In these RA patients who had not received prednisolone, the mean serum ACTH levels sharply increased after every injection of anti-TNF, which indicates a sensitization of the pituitary gland (not observed for the adrenal gland). During treatment, the ratio of serum cortisol to serum ACTH decreased, which also indicates a sensitization of the pituitary gland (P < 0.001), and which was paralleled by constant cortisol secretion. The adrenal androgen ASD significantly increased relative to its precursor 17(OH)progesterone (P = 0.013) and relative to cortisol (P = 0.009), which indicates a normalization of adrenal androgen production. The comparison of patients previously treated with prednisolone and those without previous prednisolone revealed marked differences in the central and adrenal level of this endocrine axis during long-term anti-TNF therapy. CONCLUSION: Long-term therapy with anti-TNF sensitizes the pituitary gland and improves adrenal androgen secretion in patients who have not previously received prednisolone treatment. These changes are indicative of normalization of the HPA axis and must therefore be considered as evidence of an additional antiinflammatory influence of anti-TNF treatment in patients with RA.     

Disability and patient’s appraisal of general health contribute to depressed mood in rheumatoid arthritis in a large clinical study in Japan

Abstract

The aim of this study was to evaluate the factors responsible for depressed mood in rheumatoid arthritis (RA). Clinical and laboratory measures were collected from 4558 RA patients enrolled in a large clinical cohort study for RA conducted at the Institute of Rheumatology, Tokyo Women’s Medical University (IORRA study). A two-question depressed screening included in the U.S. Preventive Services Task Force recommendation were utilized to identify “depressed patients.” A total of 1875 (41.1%) were identified as “depressed patients” who presented with symptoms suggestive of depression. Patient’s Visual Analog Scale (VAS) for general health (43.3?mm vs 24.6?mm, P < 0.0001) and pain (40.9?mm vs 23.8?mm, P < 0.0001) and the disability index scores measured by the Health Association Questionnaire (HAQ) (0.986 vs 0.574, P < 0.0001) were significantly higher in depressed patients than in nondepressed patients. The presence of three or more comorbidities (odds ratio [OR] 2.157, P < 0.0001), infection (OR 1.754, P < 0.0001), and joint surgery (OR 1.878, P < 0.0001) were significantly correlated with depressed mood in RA. The results of the Generalized Linear Model analysis showed that HAQ disability index (P < 0.0001) and patient’s VAS for general health (P < 0.0001) were also strongly and significantly associated to the response variable “probability of depressed patients.’ Patient appraisal of poor general health and greater disability were associated with depressed mood in RA.     

Anti–interleukin‐6 receptor antibody therapy favors adrenal androgen secretion in patients with rheumatoid arthritis: A randomized,double‐blind,placebo‐controlled study

Objective

Proinflammatory cytokines such as tumor necrosis factor (TNF) were demonstrated to inhibit adrenal steroidogenesis in patients with rheumatoid arthritis (RA), and this was particularly evident in the increase in adrenal androgen levels during anti‐TNF therapy. This study investigated the influence on steroidogenesis of an interleukin‐6 (IL‐6)–neutralizing strategy using IL‐6 receptor monoclonal antibodies (referred to as MRA).

Methods

In a placebo‐controlled, double‐blind, randomized study over 12 weeks in 29 patients with RA being treated with prednisolone, 13 of whom received placebo and 16 of whom received 8 mg MRA/kg body weight, the effects of MRA on serum levels of adrenocorticotropic hormone (ACTH), cortisol, 17‐hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), androstenedione (ASD), estrone, and 17β‐estradiol, as well as their respective molar ratios, were determined.

Results

MRA therapy markedly improved clinical signs of inflammation (the erythrocyte sedimentation rate, swollen joint score, and Disease Activity Score in 28 joints). Serum levels of ACTH and cortisol and the molar ratio of cortisol to ACTH did not change. Although serum levels of DHEA and DHEAS remained stable during therapy, the DHEAS:DHEA molar ratio significantly decreased in treated patients (P = 0.048). Serum levels of ASD as well as the ASD:cortisol and ASD:17OHP molar ratios increased in MRA‐treated patients (minimum P < 0.004). Serum levels of estrone and 17β‐estradiol did not change. but the estrone:ASD molar ratio (an indicator of aromatization) decreased during 12 weeks of MRA treatment (P = 0.001).

Conclusion

Neutralization of IL‐6 increases secretion of biologically active adrenal androgens in relation to that of precursor hormones and estrogens. This is another important indication that proinflammatory cytokines interfere with adrenal androgen steroidogenesis in patients with RA.

     

Inadequately low serum levels of steroid hormones in relation to interleukin‐6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis

Objective

To compare levels of steroid hormones in relation to cytokines and to study levels of cortisol or dehydroepiandrosterone (DHEA) in relation to other adrenal hormones in untreated patients with early rheumatoid arthritis (RA) and reactive arthritis (ReA) compared with healthy controls.

Methods

In a retrospective study with 34 RA patients, 46 ReA patients, and 112 healthy subjects, we measured serum levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF), adrenocorticotropic hormone (ACTH), cortisol, 17‐hydroxyprogesterone (17‐OH‐progesterone), androstenedione (ASD), DHEA, and DHEA sulfate (DHEAS).

Results

RA patients had higher serum levels of IL‐6, TNF, cortisol, and DHEA compared with ReA patients and healthy subjects, but no difference was noticed with respect to ACTH and DHEAS. However, in RA and ReA patients compared with healthy subjects, levels of ACTH, cortisol, ASD, DHEAS, and 17‐OH‐progesterone were markedly lower in relation to levels of IL‐6 and TNF. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to serum IL‐6 in RA (R_Rank = −0.582, P = 0.001) and, to a lesser extent, in ReA (R_Rank = −0.417, P = 0.011). In RA patients, the mean grip strength of both hands was positively correlated with the ratio of serum cortisol to serum IL‐6 (R_Rank = 0.472, P = 0.010). Furthermore, in these untreated patients with RA and ReA, there was a relative decrease in the secretion of 17‐OH‐progesterone, ASD, and DHEAS in relation to DHEA and cortisol. This indicates a relative predominance of the nonsulfated DHEA and cortisol in relation to all other measured adrenal steroid hormones in the early stages of these inflammatory diseases.

Conclusion

This study indicates that levels of ACTH and cortisol are relatively low in relation to levels of IL‐6 and TNF in untreated patients with early RA and ReA compared with healthy subjects. The study further demonstrates that there is a relative increase of DHEA and cortisol in relation to other adrenal hormones, such as DHEAS. This study emphasizes that adrenal steroid secretion is inadequately low in relation to inflammation. Although changes in hormone levels are similar in RA and ReA, alteration of steroidogenesis is more pronounced in RA patients than in ReA patients.

     

Disability and patient’s appraisal of general health contribute to depressed mood in rheumatoid arthritis in a large clinical study in Japan

The aim of this study was to evaluate the factors responsible for depressed mood in rheumatoid arthritis (RA). Clinical and laboratory measures were collected from 4558 RA patients enrolled in a large clinical cohort study for RA conducted at the Institute of Rheumatology, Tokyo Women's Medical University (IORRA study). A two-question depressed screening included in the U.S. Preventive Services Task Force recommendation were utilized to identify “depressed patients.” A total of 1875 (41.1%) were identified as “depressed patients” who presented with symptoms suggestive of depression. Patient's Visual Analog Scale (VAS) for general health (43.3 mm vs 24.6 mm, P < 0.0001) and pain (40.9 mm vs 23.8 mm, P < 0.0001) and the disability index scores measured by the Health Association Questionnaire (HAQ) (0.986 vs 0.574, P < 0.0001) were significantly higher in depressed patients than in nondepressed patients. The presence of three or more comorbidities (odds ratio [OR] 2.157, P < 0.0001), infection (OR 1.754, P < 0.0001), and joint surgery (OR 1.878, P < 0.0001) were significantly correlated with depressed mood in RA. The results of the Generalized Linear Model analysis showed that HAQ disability index (P < 0.0001) and patient's VAS for general health (P < 0.0001) were also strongly and significantly associated to the response variable “probability of depressed patients.” Patient appraisal of poor general health and greater disability were associated with depressed mood in RA.     

Functional and work outcomes improve in patients with rheumatoid arthritis who receive targeted,comprehensive occupational therapy

Objective

Work disability is a serious consequence of rheumatoid arthritis (RA). We conducted a 6‐month, prospective randomized controlled trial comparing assessments of function, work, coping, and disease activity in employed patients with RA receiving occupational therapy intervention versus usual care.

Methods

Employed patients with RA with increased perceived work disability risk were identified by the RA Work Instability Scale (WIS; score ≥10). Patients were stratified into medium‐ (score ≥10 and <17) and high‐risk (≥17) groups, then randomized into occupational therapy or usual care groups. Assessments were conducted at baseline and 6 months. The primary outcome was the Canadian Occupational Performance Measure (COPM), a standardized patient self‐report of function. Other outcomes included the disability index (DI) of the Health Assessment Questionnaire (HAQ); Disease Activity Score in 28 joints (DAS28); RA WIS; EuroQol Index; visual analog scales (VAS) for pain, work satisfaction, and work performance; and days missed/month. Independent sample t‐tests and Mann‐Whitney U tests were used.

Results

We recruited 32 employed patients with RA. At baseline the groups were well matched. At 6 months the improvement in the occupational therapy group was significantly greater than that in the usual care group for all functional outcomes (COPM performance P < 0.001, COPM satisfaction P < 0.001, HAQ DI P = 0.02) and most work outcomes (RA WIS [P = 0.04], VAS work satisfaction [P < 0.001], VAS work performance [P = 0.01]). Additionally, Arthritis Helplessness Index (P = 0.02), Arthritis Impact Measurement Scales II pain subscale (P = 0.03), VAS pain (P = 0.007), EuroQol Index (P = 0.02), EuroQol global (P = 0.02), and DAS28 (P = 0.03) scores significantly improved.

Conclusion

Targeted, comprehensive occupational therapy intervention improves functional and work‐related outcomes in employed RA patients at risk of work disability.     

Bone age and factors affecting skeletal maturation at diagnosis of paediatric Cushing’s disease

Paediatric Cushing’s disease (CD) is usually associated with growth retardation, but there are only few published data on skeletal maturation at diagnosis. We analysed factors contributing to skeletal maturation and final height in Asian Indian patients with paediatric CD. We conducted retrospective analysis of 48 patients (29 males; 19 females) with mean age: 14.84 years at diagnosis (range 9–19 years). A single observer using the Greulich Pyle method determined the bone age (BA) of each child. BA delay, i.e. the difference between chronological age (CA) and BA, was compared with clinical and biochemical variables. BA delay was present in 35/48 (73%) patients (mean delay 1.6 years, range 0.5–5 years) and correlated negatively with height SDS (r = −0.594, P < 0.001) and positively with CA at diagnosis (r = 0.247, P < 0.05). There was no correlation with duration of symptoms before diagnosis, basal cortisol, midnight cortisol, ACTH or percentage suppression of low dose dexamethasone suppression cortisol (LDDST). We could not demonstrate any relationship between the duration of history before diagnosis and height SDS at final height. Mean final height SDS in patients was −1.84. We found that most children with CD had delayed BA and correlated significantly with CA and height SDS at diagnosis. Early diagnosis may reduce delay in skeletal maturation and thus contribute to optimal catch-up growth.     

Adrenal Function as Assessed by Low-Dose Adrenocorticotropin Hormone Test Before and After Switching from Inhaled Beclomethasone Dipropionate to Inhaled Fluticasone Propionate

Low-dose adrenocorticotropin hormone (ACTH) tests (0.5 µg/L 73 m²) were done before and after switching from inhaled beclomethasone dipropionate to inhaled fluticasone propionate in 12 patients 33–77 years old who had mild-to-severe asthma to compare the effects of these drugs on adrenal function. Low-dose ACTH tests were performed after the subjects had received inhaled beclomethasone dipropionate (200–900 µg/day) for at least 12 wk. Treatment was then switched to inhaled fluticasone propionate (200–600 µg/day) for at least 12 wk, and a second low-dose ACTH test was done. Pulmonary function was assessed on the basis of peak expiratory flow rate (PEFR, % of predicted value). After switching treatment, the daily dose of inhaled corticosteroid decreased by about 40%. Basal serum cortisol and ACTH levels were similar with both treatments. The adrenal response, as assessed by incremental rise in the serum cortisol level (peak minus basal) after ACTH challenge, improved significantly (5.6–7.9 µg/dL, p<0.01) after switching to fluticasone. All three patients who had lower serum cortisol levels during beclomethasone treatment than during fluticasone treatment showed improvement in both the peak cortisol level and the incremental rise in cortisol. Mean morning and evening PEFRs significantly increased after switching from beclomethasone to fluticasone (morning: 71.2 to 76.0%, p<0.01; evening: 67.3 to 72.1%, both p<0.05). The diurnal variation of PEFR significantly decreased from 10.9% to 8.3% after switching treatment (p<0.01). We conclude that switching from beclomethasone to fluticasone reduces the risk of adrenal dysfunction associated with inhaled steroids and improves pulmonary function.