Untitled

A randomized controlled trial of R-salbutamol for topicaltreatment of discoid lupus erythematosusG.B.E. Jemec, S. Ullman,* M. Goodfield,  A. Bygum,à A.B. Olesen,§ J. Berth-Jones,– F. Nyberg,**M. Cramers,   J. Faergemann,àà P. Andersen,§§ A. Kuhn–– and T. Ruzicka*** Department of Dermatology, Health Sciences Faculty, University of Copenhagen, Roskilde Hospital, Køgevej 7-13, DK-4000 Roskilde, Denmark*Department of Dermatology, Bispebjerg Hospital, Copenhagen NV, Denmark Department of Dermatology, Leeds General Infirmary, Leeds, U.K.
àDepartment of Dermatology, Odense University Hospital, Odense, Denmark§Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark –Department of Dermatology, George Eliot Hospital, Nuneaton, U.K.
**Department of Dermatology, Danderyds Hospital, Stockholm, Sweden  Department of Dermatology, Viborg Hospital, Viborg, DenmarkààDepartment of Dermatology, Sahlgrenska University Hospital, Gothenburg, Sweden§§Astion Pharma A ⁄ S, Symbion Science Park, Copenhagen, Denmark ––Department of Dermatology, University of Mu¨nster, Mu¨nster, Germany***Department of Dermatology, Ludwig-Maximilian University Munich, Munich, Germany Background In a recent open pilot trial, R-salbutamol sulphate, a well-known mole- cule with anti-inflammatory effects, was tested successfully on patients with therapy-resistant discoid lupus erythematosus (DLE).
Objectives To compare the efficacy and safety of R-salbutamol cream 0Æ5% vs.
placebo on DLE lesions in a multicentre, double-blinded, randomized, placebo- Methods Thirty-seven patients with at least one newly developed DLE lesion were double blinded, lupus erythematosus, randomized randomized – 19 to the R-salbutamol cream 0Æ5% and 18 to placebo – and trea- controlled trial, salbutamol, topical treatment ted twice daily for 8 weeks. Efficacy was evaluated through scores of erythema,scaling ⁄hypertrophy and induration as well as pain and itching; general improve- Conflicts of interestG.B.E.J. and A.K. are on the clinical advisory ment scored by the investigator and global improvement scored by patients’ board and have received honoraria for studies from Results The mean area under the curve of improvement for scaling ⁄hypertrophy,pain, itching and global patient assessment was significantly better for the The study was sponsored by Astion Pharma A ⁄ S, actively treated patients as compared with placebo (scaling ⁄hypertrophy, P = 0Æ0262; pain, P = 0Æ0238; itching, P = 0Æ0135; global patient assessment, P = 0Æ045). Moreover, the percentage of patients without induration was signifi-cantly higher in the active group compared with the placebo group (P = 0Æ013),and a statistically significantly greater decrease in the size of the lesional areawas also seen in the overall analysis of the R-salbutamol-treated patients(P = 0Æ0197). No serious adverse events were reported.
Conclusions Application of R-salbutamol cream 0Æ5% was safe and well tolerated.
Statistically significant effects were seen on scaling ⁄hypertrophy, induration, painand itching as well as patient global assessment, suggesting that R-salbutamolcould be a promising new topical therapy alternative for DLE.
Discoid lupus erythematosus (DLE) is an autoimmune disease more common in women and people with dark skin.3 Clini- primarily confined to the skin.1 The prevalence of DLE has cally, DLE is characterized by well-defined, coin-shaped ery- been reported to be < 5 in 10 000 persons,2 and it most thematous plaques of varying size associated with adherent often appears in the 15–40-year age group. The disease is follicular hyperkeratosis. By removing the adherent scaling, Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1365–1370 1366 Topical R-salbutamol for DLE, G.B.E. Jemec et al.
follicle-sized keratotic spikes similar to carpet tacks can be University Hospital, Aarhus, and Department of Dermatology, seen (‘carpet tack sign’). The lesions slowly expand with Viborg Hospital, Viborg, Denmark; Department of Dermatol- active inflammation and hyperpigmentation at the periphery, ogy, Leeds General Infirmary, Leeds, and Department of Der- leaving depressed central atrophy and scarring, telangiectasia matology, George Eliot Hospital, Nuneaton, U.K.; Department and hypopigmentation. DLE can be localized with lesions typi- of Dermatology, Danderyds Hospital, Stockholm, and Depart- cally affecting the face and scalp or disseminated with lesions ment of Dermatology, Sahlgrenska University Hospital, Goth- extending below the neck. Extensive cosmetically disfiguring enburg, Sweden. Originally, two similar trials were started in involvement of the affected skin can occur and lesions of the Denmark, Sweden and the U.K. with almost identical proto- scalp are accompanied by permanent loss of hair.
cols. Each study should have included 32 patients; however, Treatment of patients with DLE may represent a challenge.4 the inclusion and exclusion criteria proved more restrictive At present, potent topical corticosteroids and systemic antima- than originally anticipated. As DLE is an uncommon disease larial agents such as hydroxychloroquine and chloroquine are the inclusion of a sufficient number of patients was difficult.
most commonly used, although other drugs, e.g. thalidomide, It was therefore decided to merge the two clinical study protocols into one study involving all sites in Denmark, reported to be effective.5–7 Generally, these therapies (includ- Sweden and the U.K. in order to have a sufficient number of ing systemic corticosteroids) have, however, limited efficacy and are associated with potential side-effects limiting their The trial was conducted according to the ethical guidelines use, particularly in long-term and preventive treatment. There- of the Declaration of Helsinki and performed according to the fore, a safe and efficacious treatment for this chronic skin dis- Good Clinical Practice guidelines. The protocols of the study were approved by the regional Ethics Committee in Denmark Salbutamol sulphate is a well-known drug, commonly used and the relevant Ethics Committees in Sweden and the U.K., in the treatment of bronchial asthma.8 It is a racemic mixture as well as by the competent authorities in each country.
of R- and S-enantiomers, but only R-salbutamol is pharmaco-logically active. R-salbutamol selectively binds to and activates b2-adrenoceptors, which are molecules on the surface of manycells. The inhibitory effect is seen primarily for CD4 cells, but Following written informed consent, 37 patients (28 women also for other leucocytes with a high density of b2-receptors and nine men; mean age 54 years, range 34–72) were such as monocytes, macrophages and Langerhans cells.9–11 included in this multicentre trial: 26 patients from the Depart- The binding of the b2-receptor agonist to these cells inhibits ments of Dermatology in Denmark, three from the Depart- activation of the expression of inflammatory genes and ments of Dermatology in Sweden, and eight from the thereby their proinflammatory cytokines, such as interleukin-2 Departments of Dermatology in the U.K. Only patients with at and interferon-c. R-salbutamol also inhibits superoxide gener- least one newly developed, sharply demarcated DLE lesion ation and peroxidase release from stimulated human granulo- (target lesion) with erythema score ‡ 1 and scaling ⁄ hyper- cytes. These effects might have therapeutic potential in trophy score ‡ 1 were included in the study. The diagnosis of inflammatory skin diseases, and it was therefore speculated DLE was evaluated clinically and confirmed by histological that this drug could play a role in the treatment of DLE. An analysis of skin biopsy specimens. Sexually active women were oil-in-water cream containing 0Æ5% of the active pharmaceut- required to be either surgically sterile or to use a secure con- ical ingredient R-salbutamol was developed and tested success- traceptive regimen. Patients were excluded if they had other fully in an open pilot trial in five patients with treatment- active skin diseases interfering with study outcome, had kerat- resistant DLE and four patients with subacute cutaneous lupus inization which might preclude effect from topical therapy erythematosus (SCLE).12 Following these encouraging results a due to the presence of an insurmountable barrier or scarring multicentre, double-blinded, randomized, placebo-controlled of the target lesion, were receiving treatment for systemic trial was conducted to substantiate these promising observa- lupus erythematosus, had other local or systemic treatment for tions further and to provide safety data.
DLE within 4 weeks prior to study start or were receivingother (local or systemic) drugs containing salbutamol within 4 weeks prior to study start. Pregnant or nursing women werealso excluded.
This was an 8-week, randomized, double-blinded, placebo-controlled phase II study conducted in nine centres in three At the baseline visit the substances were delivered to the countries, i.e. Department of Dermatology, Health Sciences patients and assessments were carried out at weeks 2, 4, 6 and 8 (see Outcome measures). The randomization list consisted Roskilde, Department of Dermatology, Bispebjerg Hospital, of randomization numbers 1–64 and uniquely assigned each Copenhagen, Department of Dermatology, Odense Univer- patient to one of the two treatments. To achieve equal distri- sity Hospital, Odense, Department of Dermatology, Aarhus bution of treatments within the investigative sites a block-wise Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1365–1370 Topical R-salbutamol for DLE, G.B.E. Jemec et al. 1367 randomization was applied. The randomization number was drawings. Moreover, plasma concentration of R-salbutamol the only information provided to the investigator; patients as was evaluated after 2 and 8 weeks of treatment, and adverse well as study investigators ⁄ outcome assessors were blinded.
No concomitant treatment with corticosteroids (local or sys- temic), antimalarial agents, thalidomide or retinoids was allowed. As the transdermal penetration of R-salbutamol inhumans was not known at the time of study start, the treated The trial was planned with a sample size based on a = 5%, area was not to exceed 100 cm2. Patients were instructed to 80% power and a 30% difference using the mean area of apply R-salbutamol cream 0Æ5% (ASF-1096; Astion, Copenha- improvement in the LCLASI score with SD < 29%. This would gen, Denmark) or placebo twice daily for 8 weeks. New tubes be achieved with 16 patients in both arms. Finally, 37 patients were administered every second week and the tubes were were randomized: 19 to R-salbutamol and 18 to placebo.
Eight patients were excluded from the per protocol (PP) anal-ysis due to violation of entry criteria (n = 2), use of prohib-ited drugs (n = 3), loss to follow up (n = 1), discontinuation due to lack of efficacy (n = 1) and discontinuation due to This clinical evaluation was based on the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), which The primary endpoint was the LCLASI index after 8 weeks had recently been developed for patients with cutaneous lupus of treatment. The statistical analysis of the primary efficacy erythematosus.13,14 The CLASI takes into account both ana- parameter was based on the area under the curve (AUC) of tomical regions (e.g. face, chest, arms) and morphological improvement in the LCLASI score after 8 weeks (scored every aspects (e.g. erythema, scaling ⁄ hypertrophy, dyspigmentation, 2 weeks) of treatment using the trapezoid rule and inferential scarring) of skin lesions as well as mucous membrane involve- statistics. Comparison between groups was done with analysis ment and diffuse or scarring alopecia. In the present study, of variance, with LCLASI as covariate and treatment as factor.
only the selected and treated skin lesions were evaluated by a Secondary endpoints were descriptive analysis only. Last obser- clinical score based on the CLASI. Therefore, a modified Local- vation carried forward was used for any missing values. No ized Cutaneous Lupus Erythematosus Disease Area and Severity interim analysis was planned or performed. Safety was pre- Index (LCLASI) was used for the assessment and included in sented without any formal statistical analysis. Intent to treat analysis was performed with all patients randomized who Results were evaluated through: (i) scores of erythema, received at least one treatment dose. The PP data set excluded scaling ⁄ hypertrophy, dyspigmentation, scarring ⁄ atrophy ⁄ pann- any major protocol violators and patients who missed more iculitis and induration (LCLASI); the sum of the erythema score, the scaling ⁄ hypertrophy score, the dyspigmentationscore and the scarring ⁄ atrophy ⁄ panniculitis score was further combined into a composite local score of disease (Table 1);(ii) investigators’ assessment of general improvement: this was assessed using a five-point scale ()1 to 3); (iii) patients’assessment of the global improvement of the treated lesion: The mean AUC of improvement for scaling ⁄ hypertrophy was this was assessed using a five-point scale ()1 to 3); (iv) assess- significantly higher for the R-salbutamol-treated patients with ment of pain and itching by the patient: this was assessed DLE compared with the placebo group after 8 weeks of treat- using a horizontal visual analogue scale from 0 (‘no pain’ ⁄ ‘no ment (P = 0Æ0262, Table 2). Induration was present in 34 of itching’) to 10 (‘worst possible pain’ ⁄ ‘worst imaginable 37 (92%) patients at baseline. The percentage of patients itching’); and (v) size of lesion by digital reading of folio where induration was absent after 8 weeks of treatment was Table 1 The Localized Cutaneous Lupus Erythematosus Disease Area and Severity Index scoring system providing a composite score of diseaseseverity and used as the primary effect variable Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1365–1370 1368 Topical R-salbutamol for DLE, G.B.E. Jemec et al.
Table 2 Mean ± SD scaling ⁄ hypertrophy score per visit for patients shown together with the area under the curve (AUC) of improvement and theP-value for the analysis of variance Absence of induration
at week 2, 4, 6 and 8
Patients (%) 20
Change from baseline
Fig 1. Induration responders (percentage of patients with induration Fig 2. Mean change from baseline in the assessment of pain (visual absent) for patient groups treated with R-salbutamol cream 0Æ5% or analogue scale score) per visit for patients treated with R-salbutamol cream 0Æ5% or placebo (intent to treat analysis).
Table 3 Overall analysis of variance of improved lesion area at week 2, 4, 6 and 8
Change from baseline
Fig 3. Mean change from baseline in the assessment of itching (visual significantly higher in the R-salbutamol group compared with analogue scale score) per visit for patients treated with R-salbutamol the placebo group (P = 0Æ013) (Fig. 1). Similarly, there was a cream 0Æ5% or placebo (intent to treat analysis).
consistent trend towards a better mean AUC of improvementin the LCLASI score for erythema (P = 0Æ5080) and the gen- lesions was significantly better in the actively treated patients eral improvement (P = 0Æ1539) scored by the investigator in compared with the placebo group (P = 0Æ006).
the R-salbutamol group compared with the placebo groupwhich, however, did not reach statistical significance (data not shown). The reduction of the size of the lesional area wassignificantly higher in the actively treated patients with DLE Analysis of blood samples for plasma level of R-salbutamol compared with the placebo group in the PP analysis set from all patients with DLE after 2 and 8 weeks of treatment showed that only one sample from one patient after 8 weeksof 0Æ1 ng mL)1. This plasma level is nearly 30 times below levels of R-salbutamol after oral administration.
The mean AUC of improvement for pain and itching was sig-nificantly better in the R-salbutamol-treated patients with DLE compared with the placebo group (pain, P = 0Æ0238; itching,P = 0Æ0135) (Figs 2 and 3). The mean AUC of improvement No serious adverse events were reported. In total, 39 adverse for the global patient assessment also reached significance events were documented in 21 patients with DLE during the between the R-salbutamol-treated patients and the placebo trial. Nine patients treated with the R-salbutamol 0Æ5% cream group (P = 0Æ045). Moreover, patient assessment of facial experienced 24 of these events while 12 patients treated with Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1365–1370 Topical R-salbutamol for DLE, G.B.E. Jemec et al. 1369 placebo experienced 15 events. The most common events unexpectedly high variation and the analysis therefore proved were headache (n = 12), back pain (n = 2), nasopharyngitis to be underpowered for the primary endpoint. It is also possi- (n = 2), impetigo (n = 2), conjunctivitis (n = 2), dyspepsia ble that an increased dosage, either through increased fre- (n = 2) and viral infection (n = 2). None of the 24 reported events in the R-salbutamol-treated patients was considered treatment time, could overcome this. Alternatively, an instru- mental assessment of changes may be of benefit in futurestudies.21 There were no safety issues encountered in the study. No serious adverse events were reported and none of the reported In the treatment of chronic recurrent diseases, it is an impor- events was considered related in the group treated with tant goal to provide a safe and efficient therapy with a mini- R-salbutamol. The most frequently reported events were head- mum potential for adverse effects. Increased knowledge about ache, back pain and nasopharyngitis. Moreover, the plasma existing drugs suggests that many agents may have broader levels of R-salbutamol after 8 weeks of treatment showed no biological effects than hitherto thought, and may therefore significant absorption from the treated lesions in this study be used to treat a wider range of diseases. R-salbutamol may and there seems to be a large window of safety regarding be such a promising drug. In addition to its well-known b2- absorption to the systemic circulation when comparing with receptor agonist action, it appears to have anti-inflammatory properties which warrants further investigation of its possible Taken altogether, R-salbutamol cream 0Æ5% showed sig- clinical utility in fields other than pulmonary medicine.
nificant effects on several single signs and symptoms of DLE Successful experimental use of an R-salbutamol cream 0Æ5% lesions (scaling ⁄ hypertrophy, induration, lesion area improve- (ASF-1096) has recently been reported in five patients with ment, pain and itching, patient global assessment); however, therapy-resistant DLE and four patients with SCLE.12 Patients there was no significance on the primary composite parame- were asked to apply 0Æ5% R-salbutamol cream on their skin ter. The preparation appeared safe and well tolerated during lesions twice daily. After initial improvement in SCLE, two the 8 weeks of twice-daily application. Further clinical testing patients developed toxic eczema after 6–8 weeks, which disap- using higher strength or longer treatment periods of R-salbu- peared under topical corticosteroids within 4–6 days. How- tamol cream or combination therapy with other treatment ever, reapplication of R-salbutamol 0Æ5% in a new formulation modalities may improve the results indicated by this trial.
resulted in clearance of the skin lesions without any side-effects. Nonhypertrophic DLE with relatively new lesions showed good response; hypertrophic lesions did not improveat the beginning of treatment, but showed some response 1 Kuhn A, Sontheimer RD. Cutaneous lupus erythematosus: molecu- after 2–3 months. This first clinical study demonstrated lar and cellular basis of clinical findings. Curr Dir Autoimmun 2008;10:119–40.
encouraging results for treatment of DLE.
2 Astion Pharma A ⁄ S. The EMEA Recommends the Drug Candidate ASF-1096 In the present randomized, double-blinded, placebo-con- for Orphan Drug Status. Press Release. Copenhagen: Astion, 2007.
trolled phase II study a significant effect of R-salbutamol 3 Costner MI, Sontheimer RD, Provost TT. Lupus erythematosus. In: cream 0Æ5% was seen on several clinical parameters including Cutaneous Manifestations of Rheumatic Diseases (Sontheimer RD, Provost scaling ⁄ hyperthrophy and induration of the DLE skin lesions TT, eds). Philadelphia: Williams & Wilkins, 2003; 15–64.
as well as pain, itching and patients’ global assessment. A 4 Sticherling M, Bonsmann G, Kuhn A. Diagnostic approach and positive trend (although not statistically significant) in the treatment of cutaneous lupus erythematosus. J Dtsch Dermatol Ges2008; 6:48–59.
LCLASI score and in the investigators’ global assessment was 5 Callen JP. Management of ‘refractory’ skin disease in patients seen compared with the placebo group. These results suggest with lupus erythematosus. Best Pract Res Clin Rheumatol 2005; a clinically meaningful effect of topical R-salbutamol on DLE and are in agreement with studies demonstrating that b-adren- 6 Clarke JT, Werth VP. Therapy of cutaneous lupus erythematosus.
ergic stimulation is disturbed in rheumatological diseases.15–17 Expert Rev Dermatol 2006; 1:105–20.
Such an influence may even play a role in stress-induced dis- 7 Heath M, Raugi GJ. Evidence-based evaluation of immunomodula- tory therapy for the cutaneous manifestations of lupus. Adv Dermatol2004; 20:257–91.
However, the primary endpoint (LCLASI score) did not 8 Prenner BM. Role of long-acting beta2-adrenergic agonists in show a positive outcome. CLASI is a newly developed scoring asthma management based on updated asthma guidelines. Curr Opin system applied to assess disease activity and damage in the entire patient.13,14 In this study, the score was adapted to the 9 Baramki D, Koester J, Anderson AJ et al. Modulation of T-cell single treated lesions and did not include the evaluation of function by (R)- and (S)-isomers of albuterol: anti-inflammatory mucous membrane lesions and alopecia. The adaptation of influences of (R)-isomers are negated in the presence of the part of the full scoring system to be applied to assessment (S)-isomer. J Allergy Clin Immunol 2002; 109:449–54.
10 Volcheck GW, Kelkar P, Bartemes KR et al. Effects of (R)- and of a single local lesion may not provide valid results. It has (S)-isomers of beta-adrenergic agonists on eosinophil response to previously been shown that adaptation of a clinical scoring interleukin-5. Clin Exp Allergy 2005; 35:1341–6.
system may be difficult.19,20 The data of our study showed an Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1365–1370 1370 Topical R-salbutamol for DLE, G.B.E. Jemec et al.
11 Leff AR, Herrnreiter A, Naclerio RM et al. Effect of enantiomeric 16 Wahle M, Kolker S, Krause A et al. Impaired catecholaminergic sig- forms of albuterol on stimulated secretion of granular protein from nalling of B lymphocytes in patients with chronic rheumatic dis- human eosinophils. Pulm Pharmacol Ther 1997; 10:97–104.
eases. Ann Rheum Dis 2001; 60:505–10.
12 Wulf HC, Ullman S. Discoid and subacute lupus erythematosus 17 Loza MJ, Peters SP, Foster S et al. Beta-agonist enhances type 2 T-cell treated with 0Æ5% R-salbutamol cream. Arch Dermatol 2007; survival and accumulation. J Allergy Clin Immunol 2007; 119:235–44.
18 Baerwald C, Graefe C, Muhl C et al. Beta 2-adrenergic receptors on 13 Bonilla-Martinez ZL, Albrecht J, Troxel AB et al. The Cutaneous peripheral blood mononuclear cells in patients with rheumatic dis- Lupus Erythematosus Disease Area and Severity Index: a responsive eases. Eur J Clin Invest 1992; 22 (Suppl. 1):42–6.
instrument to measure activity and damage in patients with cutane- 19 Jemec GB, Wulf HC. The applicability of clinical scoring systems: ous lupus erythematosus. Arch Dermatol 2008; 144:173–80.
SCORAD and PASI in psoriasis and atopic dermatitis. Acta Derm 14 Albrecht J, Taylor L, Berlin JA et al. The CLASI (Cutaneous Lupus Erythematosus Disease Area and Severity Index): an outcome 20 Holm EA, Wulf HC, Thomassen L et al. Assessment of atopic eczema: instrument for cutaneous lupus erythematosus. J Invest Dermatol clinical scoring and noninvasive measurements. Br J Dermatol 2007; 15 Pawlak CR, Jacobs R, Mikeska E et al. Patients with systemic lupus 21 Holm EA, Wulf HC, Thomassen L et al. Instrumental assessment of erythematosus differ from healthy controls in their immunological atopic eczema: validation of transepidermal water loss, stratum response to acute psychological stress. Brain Behav Immun 1999; corneum hydration, erythema, scaling, and edema. J Am Acad Dermatol Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 161, pp1365–1370

Source: http://www.codexial-dermatologie.com/upload/news/docs/45Salbutamol-LED-article.pdf