Topical tacrolimus therapy of resistant cutaneous lesions in lupus erythematosus: a possible alternative

C. E. Lampropoulos, S. Sangle, P. Harrison, G. R. V. Hughes and D. P. D'Cruz

Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, UK.

Correspondence to: D. P. D’Cruz, The Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London SE1 7EH, UK. E-mail: david.d'cruz{at}kcl.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Objective. To determine the efficacy of tacrolimus ointment 0.1% on resistant cutaneous lesions in patients with lupus erythematosus.

Methods. Twelve patients with skin manifestations were studied. Six had discoid lupus (DL), four subacute cutaneous lupus erythematosus (SCLE) and two systemic lupus erythematosus (SLE). All patients had extensive skin lesions refractory to previous treatment. Patients received topical tacrolimus 0.1% for a minimum of 6 weeks and response was evaluated by physicians’ and patients’ assessment and documented with photographs at baseline and at the end of the treatment.

Results. Eleven of 12 patients completed the therapy. One patient with DL discontinued because of side-effects—peeling and a burning sensation. Six patients were clearly improved, one patient had a minor remission of his face lesion while in four the rashes remained the same. Two patients with SCLE had significant regression of their lesions while the other two had no improvement. In DL, two had certain improvement, one minor improvement and two were without response. The patients with SLE had significant amelioration of their extensive photosensitive rash.

Conclusion. Tacrolimus ointment 0.1% may be an effective alternative in patients with severe resistant cutaneous manifestations in lupus erythematosus.

KEY WORDS: Tacrolimus, Cutaneous lupus erythematosus


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Cutaneous lesions are a common and often disfiguring manifestation of autoimmune connective tissue diseases. Cutaneous lupus erythematosus is a broad term which includes a variety of lesions such as malar, butterfly or widespread photosensitive rash, subacute cutaneous, chronic cutaneous (classical discoid lupus, lupus profundus, lupus pernio/chilblains), urticarial or purpuric vasculitis and vascular lesions (periungual erythema, livedo reticularis, Raynaud's, telangiectasia).

Administration of systemic agents such as corticosteroids, hydroxychloroquine (HCQ), mepacrine, methotrexate (MTX), mycophenolate mofetil (MMF), cyclophosphamide (CPM) and/or azathioprine (AZA) for the underlying systemic disease leads in many cases to remission of the cutaneous lesions. The results are better when topical treatment (steroids, sun protection) is used. Nevertheless, many patients suffer from resistant cutaneous lesions despite therapy. On the other hand, cutaneous lesions may be the only manifestation of the disease such as subacute cutaneous lupus erythematosus (SCLE) and discoid lupus (DL), making it difficult to justify systemic agents because of their side-effects. A variety of systemic [dapsone, thalidomide, retinoids, intravenous immunoglobulins (i.v. IG)] and topical agents (thalidomide, intralesional steroids, retinoids) as well as laser therapy, phototherapy, photopheresis and cryotherapy have been used for resistant cutaneous lesions [1].

Tacrolimus, isolated in 1984 from the fungus Streptomyces tsukubaensis, is a macrolide immunomodulator FK506, which acts on T lymphocytes and inhibits interleukin-2 transcription as well as other cytokines [2]. Since 1989 it has been widely used in preventing graft rejection after transplantation (liver, kidneys, lungs) [3]. Because of its anti-inflammatory action, in November 2000 the US FDA Dermatologic Committee [4] approved tacrolimus ointment for the treatment of moderate to severe atopic dermatitis in children and adults. Efficacy is similar or even better than that of corticosteroids (especially in children or in facial lesions where only weak steroids can be used), without the adverse effects of skin atrophy (no impairment of collagen synthesis) and serious systemic absorption [5]. Common side-effects are burning sensations, itching or erythema, which usually decline with continuance of treatment due to improvement of the skin's condition [6]. Tacrolimus also appears to be effective in resistant cutaneous lesions of other diseases such as psoriasis [7], localized scleroderma [8], chronic actinic dermatitis [9], pyoderma gangrenosum [10], Behçet's disease [11], lichen planus [12], rheumatoid ulcers [13] and steroid rosacea [14].

The aim of this preliminary study was to assess the efficacy of tacrolimus ointment on resistant cutaneous lesions in lupus erythematosus.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twelve patients participated in this study. The patient group consisted of nine women and three men with mean age of 38.2 yr, ranging from 22 to 74. All had extensive cutaneous lesions resistant to previous treatment (Table 1).


View this table:
[in this window]
[in a new window]
 
TABLE 1 Patients’ cutaneous lesions and previous treatment

 
All patients applied tacrolimus ointment 0.1% over the cutaneous lesions twice a day for at least 6 weeks. Laboratory investigation at baseline and after treatment included antinuclear anti-bodies (ANA), double-stranded deoxyribonucleic acid (ds-DNA), extractable nuclear antigens (ENA), C3, C4, anticardiolipin IgG and IgM antibodies, lupus anticoagulant, full blood count, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). The results of the treatment were evaluated after 6 weeks by clinical assessment and documented with photographs before and after treatment.

This study was approved by the St Thomas’ Hospital Ethics Committee and all patients gave full informed consent.


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Eleven of 12 patients completed the therapy. One patient with DL discontinued because of side-effects—peeling and a burning sensation. The first six patients were certainly improved (Fig. 1), the seventh patient had a minor remission of his arm lesion while in four the rashes remained the same. Two patients with SCLE had significant improvement while the other two had no improvement. In DL, two had certain improvement, one minor and two were without response. The patients with systemic lupus erythematosus (SLE) had significant amelioration of their extensive photosensitive rash.



View larger version (76K):
[in this window]
[in a new window]
 
FIG. 1 Patients’ photographs before and after treatment. This figure may be viewed in colour at Rheumatology Online.

 
Laboratory investigations showed no difference before and after treatment. This was not surprising as the ointment is rarely absorbed enough to affect the systemic disease.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Cutaneous lesions in connective tissue diseases may prove very resistant to classical systemic and topical agents. These lesions usually appear in visible areas resulting in significant psychological effects. Therapy of resistant disease is often unsatisfactory due to recalcitrant disease or serious side-effects, as with thalidomide [15].

Over the last two decades, tacrolimus has emerged as an effective immunosuppressive and anti-inflammatory agent. Its systemic use is confined to preventing allograft rejection because of potential serious side-effects. Topical tacrolimus is much safer and is very effective in severe and resistant atopic dermatitis, especially in children or on facial lesions where only weak topical steroids can be used. The ointment is expensive, but a recent cost-effectiveness analysis showed that in the long term the cost is similar for tacrolimus and high-potency topical corticosteroids [16]. Topical tacrolimus is not systemically absorbed, even when large areas of skin are affected. The most common adverse effect is a burning sensation which may settle with continued use. Recently, topical tacrolimus has been used in other chronic inflammatory conditions such as psoriasis, dermatomyositis and cutaneous lupus erythematosus. There are a few case reports suggesting a good therapeutic efficacy in SCLE, DL and SLE but the number of patients is insufficient for an objective conclusion [17, 18]. For DL patients in particular the results so far seem to be controversial [19, 20]. Other topical agents including pimecrolimus may also emerge as useful therapies but have not yet been studied in detail.

The results of our study are encouraging, particularly for SCLE and DL, which are the most resistant cutaneous lesions of lupus erythematosus. More than 50%of patients had an improvement after 6 weeks of therapy. Interestingly, two of these patients were improved after the third week of therapy, probably reflecting the chronicity of the lesions. These results, combined with the absence of serious side-effects, suggest that tacrolimus should be considered as an alternative treatment for resistant cutaneous lesions in lupus erythematosus.

The authors declare no conflicts of interest.


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

  1. Ting WW, Sontheimer RD. Local therapy for cutaneous and systemic lupus erythematosus: practical and theoretical considerations. Lupus 2001;10:171–84.[CrossRef][ISI][Medline]
  2. Homey B, Assmann T, Vohr HW et al. Topical FK506 suppresses cytokine and costimulatory molecule expression in epidermal and local draining lymph node cells during primary skin immune responses. J Immunol 1998;160:5331–40.[Abstract/Free Full Text]
  3. Starzl TE, Todo S, Fung J. FK506 for liver, kidney and pancreas transplantation. Lancet 1989;8670:1000–4.
  4. US FDA Advisory Committee recommends approval for Tacrolimus ointment. Skin Ther Lett 2000;6:5.
  5. Bos JD. Non-steroidal topical immunomodulators provide skin-selective and self-limiting treatment in atopic dermatitis. Eur J Dermatol 2003;13:455–61.[ISI][Medline]
  6. Soter NA, Fleischer AB, Webster OF. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part II, safety. Am Acad Dermatol 2001;44(Suppl 1):S39–S46.[CrossRef]
  7. Yamamoto T, Nishioka K. Topical tacrolimus: an effective therapy for facial psoriasis. Eur J Dermatol 2003;13:471–3.[ISI][Medline]
  8. Mancuso G, Berdondini RM. Topical tacrolimus in the treatment of localized scleroderma. Eur J Dermatol 2003;13:590–2.[ISI][Medline]
  9. Evans A, Palmer R, Hawk J. Erythrodermic chronic actinic dermatitis responding only to topical tacrolimus. Photodermatol Photoimmunol Photomed 2004;20:59–61.[CrossRef][ISI][Medline]
  10. Petering H, Kiehl P, Breuer C et al. Pyoderma gangrenosum: successful topical therapy with tacrolimus (FK506). Hautarzt 2001;52:47–50.[CrossRef][ISI][Medline]
  11. Sakane T, Mochizuki M, Inaba G, Masuda K. A phase 11 study of FK506 (tacrolimus) on refractory uveitis associated with Behçet's disease and allied conditions. Ryumachi 1995;35:802–13.[Medline]
  12. Lener EV, Brieva J, Schachter M et al. Successful treatment of erosive lichen planus with topical tacrolimus. Arch Dermatol 2001;137:419–22.[Free Full Text]
  13. Schuppe H, Richter-Hintz D, Stierle HE et al. Topical tacrolimus for recalcitrant leg ulcer in rheumatoid arthritis. Rheumatology 2000;39:105–6.[Free Full Text]
  14. Goldman D. Tacrolimus ointment for the treatment of steroid-induced rosacea: a preliminary report. J Am Acad Dermatol 2001; 44:995–8.[CrossRef][ISI][Medline]
  15. Karim MY, Ruiz-Irastorza G, Khamashta MA, Hughes GRV. Update on therapy—thalidomide in the treatment of lupus. Lupus 2001;10:188–92.[CrossRef][ISI][Medline]
  16. Ellis CN, Drake LA, Prendergast MM et al. Cost-effectiveness analysis of tacrolimus ointment versus high-potency topical corticosteroids in adults with moderate to severe atopic dermatitis. J Am Acad Dermatol 2003;48:553–63.[CrossRef][ISI][Medline]
  17. Druke A, Gambichler T, Altmeyer P, Freitag M, Kreuter A. 0.1% Tacrolimus ointment in a patient with subacute cutaneous lupus erythematosus. J Dermatol Treat 2004;15:63–4.[CrossRef]
  18. Bohm M, Gaubitz M, Luger TA, Metze D, Bonsmann G. Topical tacrolimus as a therapeutic adjunct in patients with cutaneous lupus erythematosus. A report of three cases. Dermatology 2003;207:381–5.[CrossRef][ISI][Medline]
  19. Walker SL, Kirby B, Chalmers RJG. The effect of topical tacrolimus on severe recalcitrant chronic discoid lupus erythematosus. Br J Dermatol 2002;147:405–6.[CrossRef][ISI][Medline]
  20. Yoshimasu T, Ohtani T, Sakamoto T, Oshima A, Furukawa F. Topical FK506 (tacrolimus) therapy for facial erythematous lesions of cutaneous lupus erythematosus and dermatomyositis. Eur J Dermatol 2002;12:50–2.[ISI][Medline]
Submitted 1 March 2004; revised version accepted 21 June 2004.