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Rheumatology Advance Access originally published online on January 31, 2008
Rheumatology 2008 47(3):334-338; doi:10.1093/rheumatology/kem342
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Testosterone patches in the management of patients with mild/moderate systemic lupus erythematosus

C. Gordon1, D. J. Wallace2, S. Shinada3, K. C. Kalunian4, L. Forbess2, G. D. Braunstein2 and M. H. Weisman2

1Department of Rheumatology, Division of Immunity and Infection, The University of Birmingham, Birmingham, UK, 2Cedars-Sinai Medical Center, Los Angeles, CA, 3University of Southern California, Los Angeles, CA and 4University of California, San Diego, La Jolla, CA, USA.

Correspondence to: C. Gordon, Department of Rheumatology, Division of Immunity and Infection (East Wing), The Medical School, University of Birmingham, Birmingham B15 2TT, UK. E-mail: p.c.gordon{at}bham.ac.uk


   Abstract
Top
 Abstract
Background
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objectives. Androgen deficiency has been associated with the development of systemic lupus erythematosus (SLE). The aim of this study was to test the efficacy of testosterone patches vs placebo in female SLE patients with baseline mild-to- moderate disease activity in a randomized, double-blind, single-centre placebo-controlled trial.

Methods. Patients received testerosterone (150 µg) or placebo transdermal patches for 12 weeks. Patients were assessed at 4-weekly intervals for disease activity using the Safety of Oestrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index (SELENA-SLEDAI), Systemic Lupus Activity Measure-Revised (SLAM-R) and The British Isles Lupus Assessment Group (BILAG) indices, physican global assessment (PGA), quality of life using the SF-36 survey and sexual functioning using the Derogatis score. Data were analysed using two sample t-tests to compare the mean difference from baseline to week 12 in the testosterone patch and placebo groups.

Results. Thirty-four patients were recruited in to each group. There was no significant baseline difference between the groups in age, race or marital status. There was no significant difference between treatment groups in the mean change in SELENA-SLEDAI (0.547 ± 3.72, P > 0.60), nor in PGA or BILAG system scores. The mean change in SLAM-R score was statistically different (2.06, S.D. 3.3, P = 0.01) but was not considered clinically meaningful. Health transition also showed a small change (P < 0.03). There was no significant difference in the Derogatis scores or toxicity.

Conclusions. Testosterone patches were safe but did not significantly affect disease activity, quality of life or sexual functioning. Increased use of steroids in the placebo group may have confounded the study results.

KEY WORDS: SLE, Lupus, Testosterone, Disease activity index, Treatment


   Background
Top
 Abstract
 Background
Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 
It has been recognized for many years that androgen deficiency can predispose to and accelerate murine lupus [1–4]. There has also been some evidence that androgen deficiency may be associated with the development of systemic lupus erythematosus (SLE) in humans [5–7]. This led to interest in the use of androgens as therapy for lupus. Testosterone has been shown to delay or prevent murine lupus in the NZB/W mouse model of lupus [1, 3, 8]. More recently, dehydroepiandrosterone (DHEA, Prasterone) has been developed as a therapy for SLE in humans [9–13]. Chang et al. [11] demonstrated that DHEA can reduce flares by 16% compared with placebo, and can lengthen time to flare. In another study, DHEA was shown to enable reduction of steroids in SLE patients [12]. In this study, Petri et al. [12] also showed that DHEA can improve or stabilize lupus without significant deterioration using the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and SLE Measure (SLAM) and patient global assessment to assess disease activity as well as the Krupp fatigue severity scale. With the development of moderately low dose testosterone patches that have been associated with improved quality of life in menopausal women [14–17], the possibility that testosterone patches might provide a convenient and non-toxic therapeutic option for SLE patients with mild/moderate disease activity was raised. The aim of this study was to compare the efficacy and safety of testosterone and placebo patches in female SLE patients with mild/moderate disease activity in a randomized, double-blind, placebo-controlled single-centre clinical trial.


   Patients and methods
Top
 Abstract
 Background
 Patients and methods
Results
 Discussion
 Acknowledgements
 References
 
In this investigation, patients were enrolled if they displayed mild- to-moderate SLE disease activity as defined by scores of 2 or greater using the Safety of Oestrogens in Lupus Erythematosus National Assessment-SLEDAI (SELENA-SLEDAI) [18]. Eligible patients were randomly assigned to either active drug or placebo. Patients received drug/placebo patches at visit 1 and were reviewed at 4, 8 and 12 weeks. The primary objectives of the study were to evaluate the efficacy, safety and tolerability of the single dose patch containing 150 µg of testosterone (Proctor and Gamble, Ohio, USA) applied to the abdomen twice weekly compared with a matching placebo patch.

Female patients with SLE (defined as four or more ACR classification criteria for SLE [19]) were recruited from the private practice of one of the authors (D.J.W.) after Institutional Review Board approval was obtained. All patients gave written informed consent and were assessed by a single investigator (D.J.W.) at screening and at each 4-weekly time-point from baseline. The duration of treatment was 12 weeks and background anti-inflammatory and immune modulating therapy was intended to remain unchanged during the study.

Disease activity assessments
Disease activity was measured by three indices: the SELENA-SLEDAI [18], SLAM-revised (SLAM-R) [20] and the British Isles Lupus Assessment Group (BILAG) index [21] and in addition, the physicians global assessment (PGA) by visual analogue scale (VAS) [22]. In addition, quality of life and health status was assessed using the Short-Form-36 (SF-36) survey [23] and sexual functioning was assessed using the Derogatis Sexual Funtioning Inventory (DSFI) [24]. To be included in the study patients had to have a SELENA-SLEDAI score of 2 or more and were anticipated not to require major change in immunosuppressive therapy over the course of the study.

The SELENA version of the SLEDAI measures disease activity within the prior 10 days [18]. It is a global composite index that includes 24 clinical and laboratory variables that are weighted by the type of manifestation but not by severity. It was developed so that persistent active disease could be recorded for those manifestations that in the original version [25] were scored only if new or recurrent (proteinuria, rash, alopecia, mucocutaneous) manifestations took place. The primary end-point for this trial was planned in advance to be a significant difference between the testosterone- and placebo-treated groups in the mean difference in SELENA-SLEDAI scores from baseline to week 12 using a two-sample t-test to compare the groups.

The SLAM is an index that also measures lupus disease activity over the prior month [26]. It is a global activity score that includes non-weighted clinical and laboratory manifestations that are graded for severity. In the revised version (SLAM-R), disease activity ranges from a minimum of 0 to a maximum of 84 and is based on the evaluation of 32 variables regarding 11 organs/systems and 8 laboratory manifestations [20]. Each variable is scored from 0 to 3 on the basis of its severity. The index has proved to be reliable, valid and sensitive to change in studies [27].

The BILAG index is a reliable and valid instrument that is based on the physician's intention to treat and records disease activity in the previous month in eight individual organ systems: general, mucocutaneous, neurological, musculoskeletal, cardiovascular, respiratory, renal and haematological [21, 28]. There are 86 items including some renal and haematology results but no immunology tests. A graded score can be calculated manually or by a computer programme [21]. Based on the premise of the physician's intention to treat in lieu of a gold standard, the score A indicates very active disease of the kind that physicians would be expected to treat with new or an increased dose of prednisolone above 20 mg/day, or start or increase in cytotoxic drugs or equivalent. The score B implies that the patient needs an increase in treatment e.g. low-dose prednisolone or symptomatic treatment with non-steroidal anti-inflammatory drugs (NSAIDs) and/or anti-malarials. The score C indicates stable or mild disease requiring only symptomatic therapy such as simple analgesics. The score D implies previous organ involvement in that system but no current disease activity and a score of E indicates that there is no current disease activity and that the system has never been involved. Weighted numerical scores have been assigned to each of the above (A = 9, B = 3, C = 1 and D or E = 0) [27], so it is also possible to calculate a global score ranging from 0 to 72 although the index was not designed to be used in this way. A severe flare is defined as an increase of any previous score to an A and a moderate flare is an increase from C, D or E to a B score in any system [29]. Response to therapy can be defined as loss of A and B scores in all systems without the development of any new A or B scores. Partial response can be defined as the loss of A scores but the persistence or development of one or more B scores while on a treatment regimen [27].

The British Lupus Integrated Prospective System (BLIPS) [21] was used to record all demographic, disease activity (SELENA-SLEDAI, SLAM-R, BILAG index), quality of life and health status (SF-36), laboratory safety (e.g. full blood count, erythrocyte sedimentation rate, creatinine, liver function tests, cholesterol) and adverse events data.

Derogatis Sexual Functioning Inventory (DSFI)
The DSFI is a 256-item self report that quantifies the nature of the current sexual functioning of the individual. It is composed of 10 subtests, which include information, experience, drive, attitude, psychological symptoms, affect, gender role definition, fantasy, body image and sexual satisfaction. The scaled scores from each subtest are combined to develop an overall DSFI score. The higher the score would indicate greater functioning in the subtest area [24, 30].

Psychological General Well-Being Index
The Psychological General Well-Being (PGWB) Index is a 22-item validated, multiple-choice questionnaire that provides scores for vitality (range 0–20), self-control (0–15), positive well-being (0–20), general health (0–15), depressed mood (0–15), anxiety (0–25) and a composite score (0–110). Lower scores indicate a more negative affective experience, while higher scores, a more positive experience) [31]. The Lorenzo pictorial rating scale was used to evaluate facial hair [32].

Sex steroid hormone levels
Total and free testosterone levels were measured in the serum obtained at baseline and following 8 or 12 weeks of treatment. All measurements were performed at Quest Diagnostics Inc. (San Juan Capistriano, CA, USA). Total testosterone was measured by radioimmunoassay following extraction and column chromatography of the serum. The lower limit was 2 ng/dl (0.0694 nmol/l). The reference range for women aged 18–49 yrs is 12–50 ng/dl (0.42–1.74 nmol/l). Percentage-free testosterone was measured by equilibrium dialysis using radiolabel methods and the free testosterone concentration calculated by multiplying the total testosterone by the percentage-free testosterone. The reference range for women aged 18–49 yrs is 0.9–7.3 pg/ml (3.12–25.3 pmol/l).

Statistical analysis
Sample size
Based on power and effect size calculations using observed changes in SLEDAI from four double blind, placebo-controlled studies, it was calculated that we would need 70 patients (35 in each group).

Analysis methods
Data analyses were conducted using SAS and two-sided P < 0.05 was considered significant. Baseline patient characteristics were compared between the two groups using chi-square test for dichotomous variables and the two-sample t-test for continuous variables. The principle of intention-to-treat analysis was applied such that all patients satisfying all pre-study entry criteria and who received at least the first patch at visit 1 after screening were included. Patients were considered evaluable for efficacy if they made at least one follow-up visit at week 4, 8 or 12 (definition of per protocol population) after starting treatment.

The primary efficacy parameter in this study was the SELENA-SLEDAI score. The differences in mean change in SLEDAI scores from baseline to week 12 for the placebo and testosterone group were compared using a two-sample t-test. The last SELENA-SLEDAI score was carried forward for patients who dropped out of the study. Means and S.D.s of SELENA-SLEDAI scores at each visit were computed.

For secondary efficacy variables, means and S.D.s were computed for results at each visit. Differences in mean change from baseline to 12 weeks were compared between the two groups using the two-sample t-test. No adjustment for multiple testing was made. These secondary efficacy variables included the BILAG total score and SLAM-R score, PGA, DSFI, PGWB and the Medical Outcome Survey SF-36 individual domains.

Change in levels of total and free testosterone from screening to week 8 or 12 were compared between the two groups using the two-sample t-test. Frequencies of adverse events were compared between the two groups using Fisher's exact test. For cholesterol levels, values at 12 weeks and change from baseline to 12 weeks were compared using the t-test. Results for the Lorenzo Pictorial Rating scale were assessed by comparing the change in the hirsutism scores between the two groups using the two-sample t-test.


   Results
Top
 Abstract
 Background
 Patients and methods
 Results
Discussion
 Acknowledgements
 References
 
Patients
Seventy-one female SLE patients were recruited. There were 42 (59%) Caucasians, 5 (7%) Afro-Americans, 6 (8%) Asians (including Orientals) and 18 (25%) of other or of mixed racial origin. The mean (± S.D.) age was 37.5 (± 8.7) yrs. Thirty-six patients were randomized to placebo and 35 patients to testosterone. There were no significant differences between the groups in age, race, disease duration, education and marital status, number of pregnancies or of miscarriages, or baseline serum total or free testosterone. Two patients in the placebo group and one patient in the testosterone group did not attend any follow-up visits. Thus, 34 patients in each group were analysed for efficacy (per protocol population) as planned. The patients were on a variety of anti-inflammatory and immunosuppressive medications for SLE appropriate for this patient population (Table 1); however, no significant difference in baseline therapies between the two groups was observed.


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  		TABLE 1. Number of patients on each type of treatment regimen at baseline

 
Disease activity
In the testosterone group, the baseline mean ± S.D. SELENA-SLEDAI score was 6.1 ± 3.2 and mean ± S.D. 12-week score was 4.8 ± 3.9. In the placebo group, the baseline mean ± S.D. SELENA-SLEDAI score was 7.1 ± 3.7 and the mean 12-week score was 6.3 ± 4.1. There was no significant difference between treatment groups in the mean ± S.D. change in SELENA-SLEDAI (0.547 ± 3.72, P > 0.60), nor in the PGA (data not shown, P > 0.11).

In the testosterone group, the baseline mean ± S.D. SLAM-R score was 8.7 ± 4.1 and mean ± S.D. 12 week score was 6.5 ± 4.1. In the placebo group, the baseline mean SLAM-R score was 8.7 ± 3.4 and the mean ± S.D. 12 week score was 8.6 ± 4.8. The mean change in SLAM-R score was statistically different for testosterone minus placebo groups (2.06 ± 3.3, P = 0.01).

There was no significant difference in the maximum BILAG system scores between the two treatment groups (Table 2), nor in the mean change in BILAG total score (data not shown, P > 0.7). During the 12-week study, in the testosterone group, nine improved (loss of all A and B scores when comparing baseline and 12-week visits), 16 had persistent activity (the same A or B scores at both time-points), five had deteriorated (new A or B scores at the 12-week visit compared with baseline) and four patients did not have significant disease activity at either time-point using the BILAG index (no A or B scores). In the placebo group, 10 showed improvement, 16 had persistent activity, six had deteriorated and two had no significant activity as measured by the BILAG index.


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  		TABLE 2. Differences in disease activity measured by the BILAG index at week 12 compared with baseline

 
Flare of lupus
Flare was defined as new A or B scores in any of the eight BILAG systems at any of the 4-weekly visits after baseline. There was no significant difference between the treatment groups in the number of patients with flares (new A or B scores assessed separately or together) at 4, 8 or 12 weeks (data not shown). Between 7 and 12 patients per group had a flare (mostly new B-level disease activity in one or more systems) at each visit.

Treatment for lupus
There was no difference in baseline background therapy between the two groups (Tables 1 and 3). There was no significant difference in steroid therapy prescribed during the study but there was a trend for more patients in the placebo group to have received additional steroids during the study (Table 4), even though background therapy was intended to have remained unchanged.


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  		TABLE 3. Steroid dose at baseline

 

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  		TABLE 4. Number of patients with change in steroid dose

 
Quality of life and health status
The only statistically significant difference in the mean change in SF-36 domain scores between treatment groups in this 12-week study was for health transition over the last year (Table 5). The difference in mean change between testosterone and placebo groups was 16.4 (S.D. 29.2, P < 0.03). However, in the testosterone group, the range for change in SF-36 scores between baseline and 12 weeks in testosterone group was wide (range –75 to 51) and the mean change was –8.3 (S.D. 27.8). For the placebo group, the mean change was +8.1 (S.D. 30.5) with a range of –50 to 100. There was even more variation in the other eight SF-36 domain scores between patients in the two treatment groups at baseline and 12 weeks, with no significant differences between the groups in the change in scores.


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  		TABLE 5. Difference in mean change in SF-36 domain scores between the placebo and testosterone groups

 
Derogatis Sexual Functioning Inventory
There were no significant differences for the various subscale scores for sexual dysfunction on the DSFI (Table 6).


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  		TABLE 6. DSFI subscale scores

 
Hormone levels
Table 7 provides the mean total and free testosterone levels at baseline during the screening phase and during therapy with either the testosterone patch or placebo patch at 8 or 12 weeks. Low testosterone levels were the rule in this lupus patient population as 42% of the testosterone group had values below the lower limit of normal at baseline. There were no significant differences between the two patch groups at baseline but there was a significant increase in both total and free testosterone in the testosterone patch group in comparison with either the baseline values or 8- or 12-week values in the placebo patch group (P < 0.001). Given the small numbers of patients in any subgroup analysis to be performed relative to testosterone levels and the large s.d.s of the primary outcome variable, we are unable to perform a meaningful analysis of the effect of individual baseline androgen levels as a predictor of response.


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  		TABLE 7. Mean total and free testosterone levels in the patients treated with 150 µg/day of transdermal testosterone or placebo at screening and during 8 or 12 weeks of treatment

 
Adverse events
There were no significant differences between the groups in toxicity experienced during the trial.


   Discussion
Top
 Abstract
 Background
 Patients and methods
 Results
 Discussion
Acknowledgements
 References
 
The investigators felt that there was rationale for the therapeutic intervention with testosterone patches at low dosage, studied in this population. The advent of testosterone patches as a treatment for menopausal women, particularly those with a premature surgically induced menopause [15] has led to interest in the use of these patches in other conditions. Further, there is evidence for androgen deficiency in women with lupus [5, 6]. Studies using DHEA as a treatment for lupus have been promising in terms of efficacy for mild/moderate lupus disease and fatigue without serious side-effects [10–12]. Attempting to control fatigue is an important goal in treating SLE patients as they often have poor quality of life associated with severe fatigue [23, 33]. Patients given testosterone may report improved quality of life [34] and find patches more convenient than tablets. This pilot study was designed to determine whether a 150 µg testosterone patch used twice weekly for 3 months could improve lupus disease activity, reduce the rate of lupus flares and improve quality of life as measured by the SF-36 health survey without inducing significant side-effects. Three methods of assessment of disease activity were used to maximize the opportunity to capture any significant change in lupus activity and all assessments were done by a single observer to avoid bias from multiple observers.

All the patients were considered to have mild/moderate lupus, not requiring a major change in therapy, with SELENA-SLEDAI scores of 2 or more at baseline. Most patients had B-level activity in one or more systems by the BILAG index. Two patients did not have any A- or B-level activity by the BILAG index at this time-point. There was no significant difference in the change in disease activity between the testosterone group and the placebo group as determined by the SELENA-SLEDAI score, BILAG total score or PGA (P > 0.11). Similarly, there was no significant difference between the groups in terms of the change in maximum BILAG system scores (A or B scores in any of the eight systems captured by the BILAG index). There was no difference in the flare rate measured by the BILAG index during the 12-week study but there was considerable variation in activity as measured by the BILAG index in both groups at all time-points, and patients did obtain additional steroid for their symptoms during the study. There was a small statistically significant difference in the mean change in SLAM-R score for testosterone minus placebo groups (2.1, S.D. 3.3, P < 0.01) at week 12 but this was not considered clinically significant given that the other methods of assessing disease activity did not show any significant change.

There were no significant differences in quality of life or fatigue (vitality) as measured by the individual domains of the SF-36 health survey between the two treatment groups with the exception of some improvement in health transition in the testosterone group. This result was hard to explain given that the relevant question in the SF-36 form refers to health over the previous year, as the study was only 12 weeks long and no other improvements in health status were observed.

It was reassuring that there were no serious adverse events and no significant differences in adverse events in general between the patients given placebo and those on testosterone. However, given that the DSFI scores did not show any significant difference either, it is possible that the dose used for this pilot study was not sufficient. Recent work has suggested that the 150 µg dose is not effective in surgically menopausal women and that 300 or 450 µg patches are more effective without significant toxicity in this patient population [14, 15]. Indeed, the mean serum total and free testosterone levels achieved in this study (39.18 ng/dl and 2.42 pg/ml, respectively) were similar to the median in bilaterally oophorectomized women receiving exogenous oral oestrogens who received the 150 µg of transdermal patch (44.5 ng/dl and 2.15 pg/ml, respectively) using the same testosterone assay methodologies [15], adding credence to the hypothesis that the lack of an effect was likely related to the low dose of transdermal testosterone used in this study.

Chronic damage associated with SLE was not assessed in this short study but in a longer study with higher doses it would be important to monitor for cardio-vascular and cerebro-vascular complications in particular, as lupus patients are at an increased risk of these complications [35]. Atherosclerosis may occur prematurely in women with SLE even without hormonal manipulation [36]. Testosterone is well known to affect the lipid profile [34] and this might cause problems in SLE patients who are already prone to dyslipidaemia and cardiovascular disease [37, 38]. Nevertheless, significant complications from testosterone patches have not been seen in menopausal women [14–17].

In conclusion, we did not find that 150 µg testosterone patches significantly affected disease activity, quality of life or sexual functioning in this group of SLE patients with mild/moderate lupus. The trial did show considerable variation in disease activity and SF-36 domain scores over 12 weeks in patients with mild/moderate lupus disease activity. Differences in employed concomitant steroid therapy between the groups, although not statistically different, may have confounded the results. In addition, our choice of mild/moderate patients to study for which no change in lupus activity was anticipated may have resulted in fewer flares and hence dampened our chances of a positive result. The small improvement in SLAM-R scores in patients treated with testosterone suggests that the patients ‘felt a bit better’ but the improvement in lupus disease activity and health status did not reach a threshold that was measured by our other composite indices of disease activity and the SF-36 health survey. The choice of testosterone dose intervention was influenced by safety concerns and may have been sub therapeutic in this patient population; a less conservative dosing approach with patients more likely to flare may be an appropriate next step. Additional studies are warranted.

Formula


   Acknowledgements
Top
 Abstract
 Background
 Patients and methods
 Results
 Discussion
 Acknowledgements
References
 
We are most grateful to Janet D. Elashoff, PhD and Meenu Sandhu, MS, for statistical advice and analysis.

Funding: Proctor and Gamble provided the testosterone patches.

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Background
 Patients and methods
 Results
 Discussion
 Acknowledgements
 References
 

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Submitted 11 June 2007; revised version accepted 19 November 2007.
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