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  • Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial

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Clinical and epidemiological research
Concise report
Effects of dehydroepiandrosterone on fatigue and well-being in women with quiescent systemic lupus erythematosus: a randomised controlled trial
  1. A Hartkamp1,2,
  2. R Geenen1,3,
  3. G L R Godaert3,
  4. M Bijl4,
  5. J W J Bijlsma1,
  6. R H W M Derksen1
  1. 1Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Department of Rheumatology, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands
  3. 3Department of Clinical & Health Psychology, Utrecht University, Utrecht, The Netherlands
  4. 4Department of Internal Medicine, Division of Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands
  1. Correspondence to Rinie Geenen, Department of Clinical & Health Psychology, Utrecht University, PO Box 80140, 3508TC Utrecht, The Netherlands; r.geenen{at}uu.nl

Abstract

Objective Dehydroepiandrosterone (DHEA) has been reported to improve fatigue and reduced well-being. Both are major problems in patients with systemic lupus erythematosus (SLE), even with quiescent disease. Low serum DHEA levels are common in SLE. The present work investigates the effects of DHEA administration on fatigue, well-being and functioning in women with inactive SLE.

Methods In a double-blind, randomised, placebo-controlled study, 60 female patients with inactive SLE received 200 mg oral DHEA or placebo. Primary outcome measures were general fatigue, depressive mood, mental well-being and physical functioning. Assessments were made before treatment, after 3, 6 and 12 months on medication, and 6 months after cessation of treatment.

Results Patients from the DHEA and placebo group improved on general fatigue (p<0.001) and mental well-being (p=0.04). There was no differential effect of DHEA. The belief that DHEA had been used was a stronger predictor for improvement of general fatigue than the actual use of DHEA (p=0.04).

Conclusions The trial does not indicate an effect of daily 200 mg oral DHEA on fatigue and well-being, and therefore DHEA treatment is not recommended in unselected female patients with quiescent SLE.

Clinical Trials Registration Number NCT00391924

https://doi.org/10.1136/ard.2009.117036

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    Introduction

    Systemic lupus erythematosus (SLE) is a connective tissue disease with clinical presentations such as inflammation of joints, skin, visceral membranes and kidneys.1 Fatigue and decreased well-being and functioning are frequent issues, even when disease activity is low.2 3 Attention has been drawn to the influence of dehydroepiandrosterone (DHEA) and its sulfate ester (DHEAS) on autoimmune diseases.4 Beneficial effects of DHEA administration on fatigue and well-being have been reported in older patients and in several disease states.4

    Androgens have anti-inflammatory properties.5 Serum DHEA(S) levels in SLE are low irrespective of glucocorticoid use.6 Beneficial effects of DHEA on fatigue and well-being in women with SLE were suggested by a small open study7 and in a study in patients on glucocorticoids.8 Our randomised double-blind placebo-controlled study was conducted in patients with quiescent SLE to avoid confounding by disease activity and intermediate or high-dose prednisone, a drug that improves perceived health9 and reduces serum DHEA(S) levels.4 We expected to find beneficial effects of daily oral administration of 200 mg DHEA on fatigue, well-being and functioning.

    Patients and methods

    Design

    The present study was a double-blind, randomised placebo-controlled clinical trial. In all, 60 female patients with SLE received 200 mg oral DHEA (Fagron, Nieuwerkerk a/d IJssel, The Netherlands) or placebo. At baseline, after 3, 6 and 12 months on study medication, and 6 months after cessation of treatment, outcome parameters were assessed.

    Participants

    Evaluation of 342 charts of patients with SLE from the departments of Rheumatology and Clinical Immunology of the University Medical Centres in Utrecht and Groningen yielded 181 potential candidates based on predefined criteria. Inclusion criteria were fulfilment of at least four American College of Rheumatology (ACR) SLE classification criteria,10 female gender and age ≥18 years. Exclusion criteria were pregnancy or wish to conceive, malignancy within the preceding 5 years, daily use of glucocorticoids >10 mg in the preceding 6 months, and abnormal thyroid stimulating hormone levels, serum creatinine levels, or liver function. The study was approved by the institutional review boards of both hospitals. Participants provided written informed consent.

    Variables

    Primary outcome measures were general fatigue, depressive mood, mental well-being and physical functioning. Fatigue was assessed with the general fatigue scale of the Multidimensional Fatigue Inventory (MFI, range 4–20).11 The Zung self-rating scale (range 20–80) was used to assess depressive mood (range 20–80).12 The RAND short form-36 (SF-36) Health Survey was used to measure mental well-being (mental component summary) and physical functioning (physical component summary).13

    Secondary outcome measures were self-reported pain (100 mm visual analogue scale (VAS)), fibromyalgia tender point count,14 SLE disease activity index (SLEDAI),15 erythrocyte sedimentation rate (ESR), haemoglobin concentration, serum C3 and C4, and serum anti-double-stranded DNA (anti-dsDNA) antibodies.

    DHEAS levels were measured using an Advantage chemiluminescense system (Nichols Institute Diagnostics, San Juan Capistrano, California, USA) and testosterone with polyclonal antibody with [1,2-3H(N)]-testosterone as tracer.16 At the 18-month visit, patients indicated whether they believed they had been using DHEA or placebo.

    Statistical analysis

    Patients were analysed on an intention-to-treat basis; for missing values the last observation was carried forward.

    Friedman and Mann–Whitney tests were used to examine anti-dsDNA antibody levels. Other primary and secondary outcome measurements were evaluated with repeated measures analysis of variance. The quadratic time effect was used to examine whether DHEA and placebo affected the outcome variables. The quadratic group × time interaction effect was used to examine whether this change was different for patients on DHEA and placebo.

    We considered the finding of a small effect (f=0.10) irrelevant, and a moderate effect (f=0.25) an overestimation of expected effects. We aimed for an inbetween effect size of f=0.175. We calculated a requirement for 2 groups of 30 patients to examine a differential effect of DHEA versus placebo administration (autocorrelation 0.25, 2-sided α-level 0.05, power 0.80, 5 repeated measurements).

    In statistical analyses with SPSS V.15.0 (SPSS, Chicago, Illinois, USA), a two-sided p value <0.05 was considered statistically significant.

    Results

    Patients

    The study flow chart is shown in supplementary figure 1. In all, 60 patients were randomly assigned to receive DHEA or placebo. One patient in the DHEA group stopped the study medication prematurely after 6 months. Her final evaluation was made 6 months later. Patient characteristics at enrolment were similar for both treatment groups (table 1).

    Figure 1
    Figure 1

    Scores (means and standard errors) of primary outcome measures in 60 patients with systemic lupus erythematosus (SLE) (n=30 dehydroepiandrosterone (DHEA) vs n=30 placebo) at baseline, and after 3, 6, 12 and 18 months. Higher scores indicate more fatigue, a better mental and physical health status and more depressive mood. At baseline, the four primary outcome variables did not differ between treatment groups (p>0.21).

    View this table:
    Table 1

    Baseline characteristics of research participants

    DHEAS and testosterone levels

    In the DHEA and placebo groups, DHEAS levels at baseline were lower in patients on glucocorticoids (DHEAS: 0.6 vs 1.9 µmol/litre for patients with and without prednisone, respectively; p=0.01; placebo: 0.8 vs 2.2 µmol/litre, respectively; p=0.002). During treatment with DHEA, mean levels of DHEAS and testosterone increased to supraphysiological values of 22.8 µmol/litre (SD 13.7) and 4.2 (SD 3.1) nmol/litre, respectively. The increase of serum levels of DHEAS after administration of DHEA was significant only in the DHEA group (p <0.001). The change in DHEAS level did not differ for patients with and without prednisone (p=0.82 for DHEA; p=0.17 for placebo).

    Primary outcomes

    Figure 1 shows the change in the four primary outcome measures for the DHEA and the placebo groups. General fatigue showed a significant change for both treatments (p<0.001): the best scores were observed during treatment. Depressive mood (p=0.04) showed a significant change for both treatment groups, with lower scores during treatment and at follow-up. For mental well-being (p=0.23) and physical functioning (p=0.06) no significant changes were found in either group.

    There was no differential effect from the study medication: the change in the primary outcome measures did not differ for the DHEA and placebo groups (p values >0.31).

    Secondary outcomes

    For three out of eight secondary outcome measures, a significant change was detected during treatment (figure 2): tender point count (p=0.003), serum C3 levels (p<0.001, lowest scores during intake of study medication) and anti-dsDNA antibodies (p<0.001, decreasing levels from baseline to 6 months after cessation of medication). For C3 levels, the change differed between the treatment groups: during the medication period, the decrease of C3 levels was most pronounced in patients treated with DHEA (p=0.03). Decreases in serum C3 levels did not correlate with changes in disease activity. Self-reported pain, SLEDAI, ESR, haemoglobin concentration and serum C4 levels did not change significantly during treatment, and there was no differential effect for the DHEA and placebo groups.

    Figure 2
    Figure 2

    Scores (means and standard errors) of 3 secondary outcome measures in 60 patients with systemic lupus erythematosus (SLE) (n=30 dehydroepiandrosterone (DHEA) vs n=30 placebo) at baseline, and after 3, 6, 12 and 18 months. At baseline, these three secondary outcome variables did not differ significantly between treatment groups (p>0.25). Not shown are the scores for self-reported pain, erythrocyte sedimentation rate, haemoglobin concentration, serum levels of complement factor 4 and anti-double-stranded DNA (dsDNA) antibodies.

    Ancillary analyses

    Of the 30 patients on DHEA, 16 and 7 believed they had used DHEA or placebo, respectively. Seven stated they were not sure. Of the 30 patients on placebo, 16 and 13 believed they had used placebo or DHEA. One was not sure. Excluding the eight patients who were not sure, we analysed the change in primary outcomes in relation to actual and believed medication used (see supplementary figure 2). The change of general fatigue (p=0.63), mental well-being (p=0.66), depressive mood (p=0.48) and physical functioning (p=0.59) did not differ with actual medication use. The change of general fatigue (p=0.04) was related to believed medication use: patients who believed they had used DHEA demonstrated an improvement. The change of mental well-being (p=0.07), depressive mood (p=0.39) and physical functioning (p=0.38) was not different with believed medication use.

    Side effects

    Androgenic side effects and disease exacerbations occurred more often with DHEA (n=5) than placebo (n=2) (see supplementary table 1).

    Discussion

    No effect of daily 200 mg oral DHEA over placebo was found on fatigue and well-being. Beneficial effects were observed with DHEA and placebo. General fatigue varied with believed instead of actual medication use.

    An open study in patients with SLE showed improvement of well-being and fatigue after a daily dose of 200 mg DHEA.7 Double-blind, placebo-controlled studies suggested a reduction of perceived disease activity17,–,19 and corticosteroid requirement.20 Studies assessing fatigue as a secondary outcome measure found no effect of DHEA.19 20 Similar to other studies,17 19 20 we found an increase of serum DHEAS and testosterone to supraphysiological levels and a decrease of serum C3 levels. Despite these physiological effects, no disease-modulating activity of DHEA was observed.

    Our study demonstrated a favourable change of fatigue and depressive mood for DHEA and placebo. Fatigue varied with belief of use instead of actual medication use. The belief that DHEA was used may have induced improvement, but it is also possible that improvement induced the belief DHEA had been used. Regression to the mean may also have played a role.

    Biological and psychological factors contribute to fatigue and mental well-being. The willingness of patients to participate in this intervention study demonstrates a positive expectation, which by itself may have increased their vitality and well-being. Our findings do not generalise to all female patients with inactive SLE and may not apply to selected patients with uniformly high fatigue levels, serum DHEAS levels below normal, prednisone treatment >10 mg/day, or patients who are postmenopausal. The size of our sample was not large enough to detect small effects or to thoroughly examine the possibility that DHEA treatment may be effective in selected patients.

    In summary, fatigue and well-being improved with DHEA and placebo administration. Therefore, our study does not support the suggestion that fatigue, well-being and functioning might be treated with daily 200 mg oral DHEA. Hence we cannot recommend DHEA substitution in unselected female patients with quiescent SLE.

    Acknowledgments

    We thank Kim Jacobs for laboratory assessments.

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    Supplementary materials

    Footnotes

    • Funding The Dutch Arthritis Association financially supported this study.

    • Competing interests None.

    • Ethics approval This study was conducted with the approval of the institutional review boards of the UMC Utrecht and the UMC Groningen, The Netherlands.

    • Provenance and peer review Not commissioned; externally peer reviewed.