Calcineurin Inhibitors

Cyclosporine (CsA) and tacrolimus (FK-506) both down-regulate T-cell activation by inhibiting calcineurin, a phosphatase required for the activation of nuclear factor of activated T cells (NFAT), a transcription factor that is required for the generation of many immunomodulating and proinflammatory cytokines. Subsequently, the synthesis of cytokines such as interferon (IFN)-y, IL-2, IL-3, IL-4, granulocyte colony-stimulating factor, and TNF-a is inhibited. CsA and tacrolimus have different cyto-plasmatic binding sites. CsA binds to cyclophylin, whereas tacrolimus connects with high affinity to FK-binding protein, which is also termed "macrophilin-12". Compared with CsA, tacrolimus exhibits a stronger immunosuppression activity.

Among other indications, CsA is approved for the treatment of rheumatoid arthritis, psoriasis, and atopic dermatitis, and its efficacy in the treatment of SLE has been reported in several studies (Caccavo et al. 1997, Manger et al. 1996). Accordingly, 10 patients with biopsy-proven membranous lupus nephropathy were treated with CsA (3.8mg/kg for at least 12 months) and a decrease in proteinuria and an improvement in serum albumin levels over more than 1 year was observed. However, one major problem of CsA treatment is nephrotoxicity, which was responsive to a dose reduction or the addition of antihypertensive drugs (Hallegua et al. 2000). Two other studies reported on 56 and 18 patients with LE being treated with CsA either as an adjunctive steroid-sparing agent or because other treatments had failed. In the study including 56 patients, only in 5.3% was renal toxicity detectable (Conti et al. 2000, Dammacco et al. 2000). According to a National Institutes of Health trial of the treatment of membranous lupus nephritis, cyclophosphamide is more effective than CsA. However, the efficacy of steroids and CsA was found to be superior compared with that of steroids alone (Austin et al. 2000). Furthermore, a study of 43 patients with lupus given CsA, 4mg/kg daily, for 4 years revealed a good response regarding thrombocytopenia but minor improvements in arthralgia, myalgia, and fatigue (Morton and Powell 2000). Unfortunately, 83% of the patients had to stop treatment because of adverse events.

Evidence from animal studies suggests that tacrolimus may have a protective effect against lupus nephritis (Entani et al. 1993). However, no data are available on the efficacy of tacrolimus in the treatment of patients with renal SLE. The efficacy of tacrolimus therapy in three patients with severe SLE whose disease had been poorly controlled by cyclophosphamide and CsA treatment has been reported (Duddrige and Powell 1997). In two of these patients, the treatment was successful; however, the third patient with cutaneous vasculitis did not experience improvement after 2 months of therapy, and administration of tacrolimus was discontinued because of nephrotoxity.

In several studies, topical tacrolimus has been shown to be an effective alternative for the treatment of atopic dermatitis as well as other inflammatory skin diseases. Systemic absorption usually is minimal, and, unlike topical corticosteroids, tacro-limus ointment does not cause skin atrophy (Paller et al. 2001). Therefore, it was tempting to evaluate the efficacy of topical tacrolimus for the treatment of CLE. In one study, 11 patients with facial skin lesions were treated with tacrolimus ointment twice daily (Yoshimasu et al. 2002). Six patients (three with SLE, one with discoid LE [DLE], and two with dermatomyositis) experienced marked regression of their skin lesion, whereas four patients (three with DLE and one with dermatomyositis) were resistant to topical therapy with tacrolimus. Therefore, the facial rash in SLE seems to improve well on local therapy with tacrolimus ointment, whereas DLE lesions seem to be more resistant. In a recent study, topical tacrolimus plus topical corticosteroids was used to treat two women with DLE resistant to antimalarials, thalidomide, and potent topical corticosteroids (Walker et al. 2002). Facial skin lesions were treated twice daily with a combination of 0.03% tacrolimus and 0.05% clobetasol propionate, and control lesions were treated with clobetasol monotherapy. The combined application of tacrolimus and a steroid resulted in a significant improvement within 10 days. In contrast, lesions treated with a topical steroid only did not significantly improve. Tapering off topical tacrolimus administration resulted in recurrence of the skin lesion, but on subsequent resumption of local tacrolimus therapy twice daily, DLE lesions improved again. Moreover, one of these patients discontinued concomitant hydroxychloroquine therapy and reduced the prednisolone dosage from 12.5 to 5.0 mg daily without relapse.

The macrolactam ascomycin derivate pimecrolimus, like tacrolimus, binds to some cytoplasmic proteins and also functions as a calcineurin inhibitor. One of the striking features of pimecrolimus is its preferential distribution to the skin and other epithelial tissues. Pimecrolimus has been introduced for the topical treatment of atopic dermatitis, and, according to preliminary data, this compound also seems to be suited for the treatment of inflammatory skin diseases such a psoriasis, hand eczema, seborrhoic eczema, and rosacea. Currently, there is only limited experience on the efficacy of pimecrolimus cream in CLE. Pimecrolimus also has been developed as an oral drug, and a first clinical trial with this compound has shown high efficacy in the treatment of psoriasis (Tomi and Luger 2002). In this 4-week dose-finding study, patients receiving 40 or 60 mg of pimecrolimus by mouth daily experienced a 60% or 75% improvement in the Psoriasis Area and Severity Index score, respectively, and, in contrast to tacrolimus or CsA therapy, no severe side effects such as nephrotoxicity were observed (Rappersberger et al. 2000). Further clinical trials are currently being performed to prove the efficacy and safety of oral pimecrolimus in the treatment of inflammatory skin diseases. Because of its high affinity to the skin and its low toxic-ity, this drug in the future may turn out to be very well suited for the treatment of LE.

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