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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

Background : Dehydroepiandrosterone is a steroid hormone used as an ‘over-the-counter’ drug in the USA. Treatment with dehydroepiandrosterone was effective in randomized controlled trials in patients with systemic lupus erythematosus. Dehydroepiandrosterone sulphate concentrations are decreased in patients with inflammatory bowel disease. Dehydroepiandrosterone inhibits nuclear factor-κB and the secretion of interleukin-6 and interleukin-12 via the peroxisome proliferator-activated receptor α.

Aim : A phase II pilot trial was started to evaluate the effect of dehydroepiandrosterone in active inflammatory bowel disease.

Methods : Twenty patients with chronic active inflammatory bowel disease [seven Crohn's disease (Crohn's disease activity index, 242 ± 51; mean ± s.d.); 13 ulcerative colitis (clinical activity index, 7.8 ± 2.1)] took 200 mg dehydroepiandrosterone per day orally for 56 days.

Results : Six of the seven patients with Crohn's disease and eight of the 13 patients with ulcerative colitis responded to treatment, with a decrease in the Crohn's disease activity index of > 70 points and a decrease in the clinical activity index of > 4 points, respectively. Six Crohn's disease patients and six ulcerative colitis patients went into remission (Crohn's disease activity index < 150; clinical activity index ≤ 4). No patient withdrew from the study because of side-effects.

Conclusions : In a pilot study, dehydroepiandrosterone was effective and safe in patients with refractory Crohn's disease or ulcerative colitis. Adjustment of the dehydroepiandrosterone dosage may further improve the treatment success.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

Dehydroepiandrosterone (DHEA) and its sulphated metabolite, dehydroepiandrosterone sulphate (DHEAS), are the most abundant steroid hormones in the body. They are predominantly synthesized in the adrenal glands in response to adrenocorticotropin, from its precursors cholesterol and pregnenolone, and can be further metabolized via androstenedione into oestrone and via testosterone into 17β-oestradiol.1 The secretion of pro-inflammatory cytokines, such as interleukin-6 and interleukin-12, and the activation of nuclear factor-κB are increased in patients with inflammatory bowel disease. Recently, it has been shown that DHEA inhibits the activation of nuclear factor-κB and the secretion of interleukin-6 and interleukin-12 via the activation of peroxisome proliferator-activated receptor α.2, 3 Furthermore, DHEA stimulates the production of interleukin-10 in murine spleen cells.4

Treatment with 50–200 mg/day DHEA has been shown to be effective in patients with lupus erythematosus.5–10 We and others have shown previously that DHEAS concentrations are decreased in patients with inflammatory bowel disease,11, 12 and that DHEAS inhibits the production of interleukin-6 by human peripheral blood monocytes.2 We therefore started a phase II pilot trial in patients with active inflammatory bowel disease refractory to other drugs.

Patients and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

Patients aged ≥ 18 years and ≤ 45 years with definitive Crohn's disease or ulcerative colitis (diagnosis for at least 6 months) were eligible. Only patients with active disease [Crohn's disease activity index (CDAI) > 150 and clinical activity index (CAI) > 4, respectively] were enrolled.13–15 The CAI incorporates eight items(Table 1). Scores on this index can range from zero to 32. Higher scores indicate more severe disease activity. A score of four or less is considered to indicate inactive disease and a decrease of ≥ 4 points is considered to be clinically relevant.14 The following exclusion criteria were applied: (i) severe Crohn's disease or ulcerative colitis presumably requiring surgery (e.g. severe bleeding, ileus, peritonitis, etc.); (ii) non-inflammatory stricture in Crohn's disease; (iii) pregnancy and nursing; (iv) bacterial or viral infection; and (v) other relevant diseases requiring specific treatment. Written informed consent was obtained from each patient. The study was performed in accordance with the Declaration of Helsinki and was approved by the ethical committee of the University of Regensburg.

Table 1.  Clinical activity index for ulcerative colitis
Clinical activity index Score
Number of liquid or very soft< 180
 stools in the 7 days preceding  the assessment18–351
36–602
> 603
Blood in stoolsNo0
Little2
Much4
Clinical assessment of general  well-beingGood0
Moderate1
Bad2
Very bad3
Abdominal cramps and painNo0
Moderate1
Bad2
Very bad3
Fever caused by colitis> 38 °C3
Extra-intestinal manifestationsIritis3
Erythema nodosum3
Arthritis3
Erythrocyte sedimentation rate> 50 mm/h1
> 100 mm/h2
Haemoglobin< 10 g/dL4

The primary study aim was the remission of Crohn's disease (defined as CDAI < 150) or ulcerative colitis (defined as CAI ≤ 4) during the study period. Secondary outcome parameters were a clinical response (decrease of CDAI > 70 or CAI ≥ 4), the relationship between response and serum concentrations of DHEAS, and safety.

Seven patients (four male, three female) with active Crohn's disease [CDAI = 242 ± 51 (mean ± s.d.); range, 161–309] and 13 patients (three male, 10 female) with active ulcerative colitis [CAI = 8.1 ± 2.0 (mean ± s.d.); range, 5–12], refractory to other drugs, were treated orally with 1 × 200 mg DHEA (Audor Pharma, Regensburg, Germany) per day for 56 days. The baseline characteristics of the patients are listed in Table 2.

Table 2.  Patient characteristics at study entry
CharacteristicCrohn's diseaseUlcerative colitis
  • DHEA, dehydroepiandrosterone.

  • Mean ± standard deviation.

Number of patients713
Sex (female/male)3/410/3
Age (years)*37.9 ± 6.331.2 ± 7.1
Disease duration (months)*131 ± 7293 ± 89
Disease location (Crohn's disease)
 Upper gastrointestinal1 (14%) 
 Terminal/neoterminal ileum6 (86%) 
 Colon/rectum4 (57%) 
Disease location (ulcerative colitis)
 Left-sided 8 (62%)
 Pan-colitis or subtotal colitis 5 (38%)
Presence of extra-intestinal manifestations6 (86%)5 (38%)
Crohn's disease activity index*13242 ± 51 
Rachmilewitz index*15 8.1 ± 2.0
Basal plasma DHEAs (mg/L)*0.76 ± 0.850.67 ± 0.72

Four of the seven patients with Crohn's disease used 5-aminosalicylic acid (3–4 g/day), six glucocorticosteroids (methylprednisolone, 4 mg/day; prednisolone, 5–10 mg/day; hydrocortisone, 100 mg/day; or budesonide, 9–18 mg/day) and two azathioprine (200 mg/day) with no response.

All ulcerative colitis patients had been refractory to at least one of the following drugs. Seven of the 13 patients with ulcerative colitis used 5-aminosalicylic acid (1.5–4 g/day), one sulfasalazine (2.5 g/day), one methylprednisolone (20 mg/day), two budesonide (1.5–3.0 mg/day), one salai guggal (H15) and E. coli Nissle 1917 (100 mg/day) and two azathioprine (150 mg/day). All medications for Crohn's disease and ulcerative colitis were kept stable 2 weeks prior to and during the study.

Intervention and follow-up schedule

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

At study entry, baseline demographic data, disease activity and baseline safety parameters were assessed. Patients were followed up after 7, 14, 28 and 56 days (end of treatment) and at 8 weeks after the end of treatment. At each visit, the CDAI and CAI scores were calculated, blood was obtained for chemical analyses, and safety parameters, side-effects and patient compliance were assessed. The study medication was discontinued if treatment failure or adverse drug reactions occurred. Treatment failure was defined as an increase in CDAI to > 350 or CAI to ≥ 12 during the study or by the need for the prescription of a new treatment for active Crohn's disease or ulcerative colitis. The need for surgery, occurrence of complications and drop-out because of severe side-effects were also defined as treatment failure. Five patients (one with Crohn's disease and four with ulcerative colitis) discontinued treatment with DHEA because of non-compliance (one) or treatment failure (four), and ended the study early according to the study protocol. One patient with Crohn's disease and two patients with ulcerative colitis did not reappear at day 56. Therefore, for these patients, the last values were carried forward for the statistical analysis.

Statistics

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

Baseline characteristics were analysed with the use of descriptive statistics. No sample size analysis was performed, as this is the first pilot trial with DHEA in inflammatory bowel disease and no information was available about the potential therapeutic effect. The analysis of efficacy was performed according to the intention-to-treat method, and included all patients who received at least one dose of DHEA and who had at least one follow-up visit.

All data are expressed as the mean ± s.d. unless otherwise indicated. Statistical analyses were performed with SPSS and CIA software. The Wilcoxon rank sum test was used for the non-parametric data. A two-sided P value of 0.05 or less was considered to indicate statistical significance.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

Serum concentrations of DHEAS increased significantly during the treatment period from 0.50 ± 0.61 mg/L to 8.1 ± 5.7 mg/L (P < 0.001) in female patients and from 1.21 ± 0.81 mg/L to 9.29 ± 4.94 mg/L (P = 0.0012) in male patients. Normal values for DHEAS in serum are 0.35–4.3 mg/L and 0.8–5.6 mg/L for females and males, respectively.

In the Crohn's disease group, six of the seven patients responded to treatment with a decrease in CDAI of ≥ 70 points (Figure 1A). All six went into remission (CDAI < 150). The mean CDAI decreased from 242 ± 51 to 111 ± 106 (P = 0.012). One patient withdrew within the first week and was considered as a non-responder. The mean number of liquid stools decreased from 5.9 ± 2.0/day to 4.3 ± 2.0/day (P = 0.16). Bloody diarrhoea and abdominal pain also decreased from grade 1.3 ± 0.5 to 1.1 ± 0.4 (P = 0.71) and from grade 1.4 ± 0.5 to 0.9 ± 1.1 (P = 0.32), respectively. C-reactive protein decreased from 20.3 ± 25.1 mg/L to 9.7 ± 11.4 mg/L (P = 0.38).

image

Figure 1. (A) Crohn's disease activity index (CDAI) values during the trial. One patient who did not respond withdrew early. (B) Clinical activity index (CAI) values during the trial. Four patients who did not respond or relapsed (patients 1, 2, 3 and 10) were lost to follow-up. For better visibility, some symbols are shifted 0.1 CAI points up or down in the figure.

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Eight of the 13 patients with ulcerative colitis responded to treatment with a decrease in CAI of ≥ 4 points (Figure 1B). Six went into remission (CAI ≤ 4). The mean CAI decreased from 7.8 ± 2.1 to 3.7 ± 3.7 (P = 0.0018). Five patients did not respond. The mean number of liquid stools decreased from 7.7 ± 3.0/day to 4.1 ± 2.5/day (P = 0.0042). Bloody diarrhoea and abdominal pain also decreased from grade 2.4 ± 0.5 to 1.5 ± 0.7 (P = 0.006) and from grade 1.0 ± 0.9 to 0.6 ± 0.9 (P = 0.23), respectively.

In patients with ulcerative colitis, there was a negative correlation between the DHEAS concentration in serum after 4 weeks of treatment and the CAI values at day 56 (Figure 2; r = − 0.656, P = 0.055).

image

Figure 2. Correlation between serum dehydroepiandrosterone sulphate (DHEAS) concentrations at day 28 (mg/L) and clinical activity index (CAI) values at day 56 (next visit) in patients with ulcerative colitis ( r  = − 0.656, P  = 0.055) . The lines indicate linear regression and 95% confidence intervals. In four of the 12 patients, no CAI values were available due to loss to follow-up at day 56.

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One patient with Crohn's disease and three patients with ulcerative colitis relapsed. The Crohn's disease patient relapsed at day 56. One patient with ulcerative colitis relapsed at day 45 and two during the follow-up to day 112, in spite of continuation of their standard medication, indicating a severe course of their disease.

Adverse events

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

No patient withdrew from the study because of side-effects. One patient with Crohn's disease had a severe adverse event, which was an unrelated fracture of the femur. One patient with ulcerative colitis had slightly elevated liver enzymes for a long time and was diagnosed with primary sclerosing cholangitis by endoscopic retrograde cholangiopancreatography. This was considered to be an unrelated severe adverse event. Only minimal adverse events, such as intermittent nausea, intermittent symptoms of a cold, intermittent herpes labialis, perioral dermatitis, subjective feeling of aggressiveness and intermittent hoarseness, occurred. All resolved during or shortly after treatment with DHEA. During treatment, no clinical masculinization was observed.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References

Treatment with DHEA was safe and effective in this pilot trial in patients with refractory active Crohn's disease or ulcerative colitis. As this is the first study using DHEA for the treatment of patients with inflammatory bowel disease, we did not include a placebo group or endoscopic examinations. Therefore, the exact effect of DHEA cannot be determined in this study. However, for patients with Crohn's disease, clinical disease activity is more important than the endoscopic response, which often does not correlate with the clinical activity.16 The placebo response is quite low in patients refractory to standard treatment, as shown recently in other trials in Crohn's disease: Present et al., Targan et al. and van Deventer et al. found placebo response rates of 8%,17 23%14 and 4%,18 respectively. These rates are markedly lower than the remission and response rates of 85.7%[confidence interval (CI), 42.1–99.6] observed in our patients with Crohn's disease. Ilnyckyj et al. have quantified the placebo response in 38 placebo-controlled treatment studies of active ulcerative colitis.19 They found that the clinical remission rate was 9.1% (CI, 6.6–11.6) and the benefit rate was 26.7% (CI, 24.1–29.2). These are also markedly lower than the remission rate of 46.2% (CI, 19.2–74.9) and the response rate of 61.5% (CI, 31.6–86.1) observed in our patients with ulcerative colitis after treatment with DHEA. As our patients had been treated previously with other drugs without effect, it can be assumed that our study population was comparable with that in the Crohn's disease studies quoted above, and more severely ill than the patients included in most of the placebo-controlled trials for ulcerative colitis analysed by Ilnyckyj et al. This is supported by the early relapses observed after the end of the study, in spite of the continuation of the patients' standard medication. This suggests that the placebo response of our patients should not be higher than that described in the trials mentioned above. However, due to the unblind nature of the trial and the small number of patients, these findings need to be confirmed in a larger placebo-controlled trial.

We did not include different doses of DHEA in this pilot trial. We used a dose of 200 mg/day in all patients. This dose was chosen because it has been used with success previously in systemic lupus erythematosus trials.5, 6, 8 However, we analysed the serum levels of DHEAS, which is the major storage form of DHEA in the body, at 28 days of treatment and correlated these values with CAI at day 56 of treatment in patients with ulcerative colitis. Interestingly, we found a significant negative correlation, indicating that the adjustment of treatment according to DHEAS serum concentrations may further improve the treatment success.

DHEA is a safe drug, and is used extensively as an ‘over-the-counter’ drug in the USA. Drug-attributable side-effects were minimal in our trial. Side-effects were also minimal in a recent, large, prospective, double-blind, placebo-controlled trial of female patients with lupus erythematosus.20 In this trial, acne was the most common adverse event, but was generally mild. Clinical and laboratory changes primarily reflected the androgenic effects of DHEA. In this study, DHEA showed a significant effect (P = 0.031) on the response in patients with active disease.

Thus, a randomized controlled trial is warranted to confirm our preliminary data in inflammatory bowel disease. In this trial, which hopefully will be started soon, we shall include measurements of pro- and anti-inflammatory cytokines to test our hypothesis that DHEA suppresses the production of interleukin-6, interleukin-12 and nuclear factor-κB and stimulates the production of interleukin-10, as has been shown previously by us and others.2–4 These inflammatory mediators have been shown to be important in the aetiology and pathogenesis of inflammatory bowel disease.

DHEA may be a safe and cheap alternative to other drugs for inflammatory bowel disease, such as azathioprine, ciclosporin A and tacrolimus, for some patients.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Patients and methods
  5. Intervention and follow-up schedule
  6. Statistics
  7. Results
  8. Adverse events
  9. Discussion
  10. References
  • 1
    Kroboth PD, Salek FS, Pittenger AL, Fabian TJ, Frye RF. DHEA and DHEA-S: a review. J Clin Pharmacol 1999; 39(4): 32748.
  • 2
    Straub RH, Konecna L, Hrach S, et al. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998; 83(6): 20127.
  • 3
    Poynter ME, Daynes RA. Peroxisome proliferator-activated receptor alpha activation modulates cellular redox status, represses nuclear factor-kappaB signaling, and reduces inflammatory cytokine production in aging. J Biol Chem 1998; 273(49): 32 833–41.
  • 4
    Cheng GF, Tseng J. Regulation of murine interleukin-10 production by dehydroepiandrosterone. J Interferon Cytokine Res 2000; 20(5): 4718.
  • 5
    Van Vollenhoven RF, Engleman EG, McGuire JL. An open study of dehydroepiandrosterone in systemic lupus erythematosus. Arthritis Rheum 1994; 37(9): 130510.
  • 6
    Van Vollenhoven RF, Engleman EG, McGuire JL. Dehydroepiandrosterone in systemic lupus erythematosus. Results of a double-blind, placebo-controlled, randomized clinical trial. Arthritis Rheum 1995; 38(12): 182631.
  • 7
    Van Vollenhoven RF, Morabito LM, Engleman EG, McGuire JL. Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol 1998; 25(2): 2859.
  • 8
    Van Vollenhoven RF, Park JL, Genovese MC, West JP, McGuire JL. A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus. Lupus 1999; 8(3): 1817.
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    Mease PJ, Merril JT, Lahita RG, et al. GL701 (prasterone, dehydroepiandrosterone) improves systemic lupus erythematosus. Arthritis Rheum 2000; 43(9): 271.
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    Chang D-M, Lan JL, Lock G, Luo SF. Dehydroepiandrosterone treatment of women with mild to moderate systemic lupus erythematosus: a multi-center, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 29247.
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    Straub RH, Vogl D, Gross V, Lang B, Schölmerich J, Andus T. Association of humoral markers of inflammation and dehydroepiandrosterone sulfate or cortisol serum levels in patients with chronic inflammatory bowel disease. Am J Gastroenterol 1998; 93(11): 2197202.
    Direct Link:
  • 12
    De TB, Hedman M, Befrits R. Blood and tissue dehydroepiandrosterone sulphate levels and their relationship to chronic inflammatory bowel disease. Clin Exp Rheumatol 1998; 16(5): 57982.
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    Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70(3): 43944.
  • 14
    Targan SR, Hanauer SB, Van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med 1997; 337(15): 102935.
  • 15
    Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. Br Med J 1989; 298: 826.
  • 16
    Modigliani R, Mary JY, Simon JF, et al. Clinical, biological, and endoscopic picture of attacks of Crohn's disease. Evolution on prednisolone. Groupe d'Etude Therapeutique des Affections Inflammatoires Digestives. Gastroenterology 1990; 98(4): 8118.
  • 17
    Present DH, Korelitz BI, Wisch N, Glass JL, Sachar DB, Pasternack BS. Treatment of Crohn's disease with 6-mercaptopurine. A long-term, randomized, double-blind study. N Engl J Med 1980; 302(18): 9817.
  • 18
    Van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intravenous interleukin 10 in steroid-refractory Crohn's disease. Crohn's Disease Study Group. Gastroenterology 1997; 113(2): 3839.
  • 19
    Ilnyckyj A, Shanahan F, Anton PA, Cheang M, Bernstein CN. Quantification of the placebo response in ulcerative colitis. Gastroenterology 1997; 112(6): 18548.
  • 20
    Petri MA, Lahita RG, Van Vollenhoven RF, et al. GL601 Study Group. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2002; 46: 8209.