The protein kinase C inhibitor AEB071 (sotrastaurin) modulates migration and superoxide anion production by human neutrophils in vitro.

We examined the effect of the protein kinase C-selective inhibitor AEB071 (sotrastaurin) on neutrophil functions in vitro. Pre-incubation with AEB071 at concentrations similar to those reached during in vivo therapy significantly reduced cell capacity to migrate toward three different chemo-attractants and to produce superoxide anions (O2⁻) in response to phorbol myristate acetate (PMA) or to N-formyl-methionyl-leucyl-phenylalanine (fMLP). AEB071 also significantly inhibited the O2⁻ overproduction induced by fMLP in neutrophils primed with tumor necrosis factor alpha (TNF-α) or granulocyte/macrophage-colony stimulating factor (GM-CSF). This inhibition was not linked to fMLP-receptor down-regulation since the drug had no effect on either fMLP-receptors or fMLP-induced CD11b membrane expression. When the activity of AEB071 was compared to that of the conventional protein kinase C (PKC) inhibitor Gö6850 (which, like sotrastaurin, inhibits classical and novel PKC isoforms), Gö6976 (an inhibitor of α and α PKC isoforms) and rottlerin (a prevailing δ PKC isoform inhibitor), AEB071 at an equimolar concentration of 3 µM (close to the maximum drug concentration reached in patients treated with AEB071) caused significantly more inhibition on both chemotactic response and superoxide production. These in vitro findings suggest that neutrophils may offer a cellular target for AEB071 activity in vivo.

Successful cyclosporine treatment in a case of amicrobial pustulosis associated with immunological abnormalities.

Amicrobial pustulosis associated with autoimmune diseases (APAD) is a clinical entity which was described only recently and few cases are reported in the literature. This condition is characterized by recurrent acute onset with pustular lesions predominantly involving skin folds, genitals, scalp and external auditory canals of young women. The etiopathogenesis of APAD is unknown and the most effective therapeutic treatment seems to be systemic corticosteroids. We describe the case of a 16-year old female patient suffering from APAD successfully treated with cyclosporine A.

Effect of Efalizumab on neutrophil and monocyte functions in patients with psoriasis.

We evaluated the effect of efalizumab on neutrophil and monocyte functions. The in vitro pre-incubation with efalizumab concentrations similar to those reached during in vivo therapy almost completely saturated CD11a binding sites without affecting the membrane expression of CD11b, CD128a or CD128b. There was a significant reduction in the chemotactic activity of the pre-treated cells toward three different chemo-attractants, whereas their phagocytic capacity and production of oxygen radicals remained unchanged. One month after the administration of efalizumab to five patients with psoriasis (T1) circulating neutrophil counts increased by 34% from pre-therapy (T0) with no change in the number of monocytes. In the same patients the CD11a binding sites on phagocytes were >90% saturated, and there was also a significant down-modulation on neutrophils (44% of T0) and monocytes (63% of T0). In line with in vitro results, efalizumab treatment caused a significant deficiency in the chemotactic properties of neutrophils and monocytes, but no changes in phagocytosis, oxidative burst, production of pro-inflammatory cytokines or the membrane expression of CD11b, CD128a and CD128b. Our findings suggest that neutrophils and monocytes may be among the targets of efalizumab activity in patients with psoriasis.

Severe psoriasis treated with a new macrolide: everolimus.

Psoriasis is an immune-mediated disease with a chronic relapsing course, and the particularly severe forms that are refractory to traditional therapies are often difficult to manage. Everolimus (Certican; Novartis, Basel, Switzerland) is a new rapamycin-derived macrolide that is used in the prophylaxis of rejection in heart and kidney transplant patients. The mechanism underlying its immunosuppressant and antiproliferative activity is different from, but complementary to, that of calcineurin inhibitors such as ciclosporin. We describe a woman with severe psoriasis treated with everolimus combined with subtherapeutic doses of ciclosporin.

Disseminated granuloma annulare: efficacy of cyclosporine therapy.

Granuloma annulare is an anatomo-clinical entity that is frequently encountered in everyday dermatological practice. We report our experience regarding 4 patients with disseminated granuloma annulare. Each patient was treated with a cycle of cyclosporine therapy for six weeks. A cycle of systemic cyclosporine therapy was started at a dose of 4 mg/kg/day for four weeks, subsequently reduced by 0.5 mg/kg/day every two weeks. The clinical picture more or less completely resolved within three weeks in all of the patients, and there were no relapses during the dose-tapering period or the following 12 months. Cyclosporine was optimally tolerated by all four patients, none of whom experienced any therapy-related side effects. Cyclosporine is a valid therapeutic option for the treatment of disseminated granuloma annulare, although we recommend its use in a protected hospital environment that facilitates patient monitoring.

Association of cyclosporine and 311 nM UVB in the treatment of moderate to severe forms of psoriasis: a new strategic approach.

Psoriasis is a T-lymphocyte mediated autoimmune disease. The response to therapies targeting T-lymphocytes suggest that the latter is a key cell in the pathogenesis of the disease. Cyclosporine (CsA) inhibits the proliferation and the IL-2 dependent expansion of T-lymphocytes. Ultraviolet radiation is an effective treatment for psoriasis. Several studies have demonstrated a significant improvement of the therapeutic response when narrow-band radiation is issued by TL-01 fluorescent lamp compared to broad- band UVB issued by other fluorescent sources. The effects of UVB on the immune system appear to be limited to the cell-mediated compartment of the immune response. In order to reduce the cumulative dose of UVB and limit the toxicity of drugs in the therapy of psoriasis, phototherapy with UVB has been used as treatment in association with other standard therapies. The purpose of the study is to evaluate, in patients with moderate to severe psoriasis a combined therapy with Cyclosporine A and 311 nm UVB phototherapy.

Mycosis on mycosis fungoides: zoophilic dermatophytosis selectively superimposed on pre-existing cutaneous T-cell lymphoma (mycosis fungoides) plaques.

We report a case of tinea corporis caused by a cattle-derived strain of Trichophyton mentagrophytes in a 44-year-old male affected by cutaneous T-cell lymphoma (CTCL, so-called mycosis fungoides). Fungal colonization of glabrous skin was strictly confined within pre-existing lymphomatous plaques. Either oral itraconazole or griseofulvin, or topical terbinafine were ineffective until the patient, who was treated with systemic retinoids and interferon-alpha for his CTCL, was shifted from leucocyte to lymphoblastoid interferon. The hypothesis that a local immunodisturbance could be responsible for the selective superimposition of tinea on CTCL lesions ('mycosis on mycosis'), and that such an immunodisturbance could be partially corrected by the interferon switch is discussed.

Sarcoidosis presenting as erythema annulare centrifugum.

Erythema annulare centrifugum (EAC), a disease belonging to the poorly characterized category of 'figurate erythemas', has been associated with a variety of conditions, such as connective tissue diseases, infections, neoplasms and drug reactions. Here we report a case of EAC associated with sarcoidosis, the first case in the literature to our knowledge. EAC was the sole sign of the granulomatous disease process, which was diagnosed by means of appropriate investigations only after the patient reported the sudden resolution of a long-standing sensitization to perfumes and parabens. Steroid treatment for sarcoidosis improved the patient's condition, and restored the allergic response to these substances.

Intramuscular low dose alpha-2B interferon and etretinate for treatment of mycosis fungoides.

BACKGROUND: Mycosis fungoides is a lymphoma of cutaneous origin characterized by a proliferation of cells with a T phenotype. METHODS: In this pilot study, 13 men with mycosis fungoides in various stages were treated with alpha-2b interferon and etretinate. RESULTS: In ten of them, such a therapy proved to be effective (7 complete responses, 3 partial responses), sometimes with prolonged remissions (up to 20 months, and still persistent) after suspension of the drugs. CONCLUSIONS: We chose low-dose interferon administration in order to prevent side effects, which are said to be dose-dependent. In our experience this is not true, but this drawback seems to be overcome by the very good, sometimes spectacular, response to this combination therapy, particularly in low stage forms of the disease. This fact, compared with results provided by other groups, prompts us to plan new research protocols based on associations of retinoids with different interferon types (or even associations of different interferons), because we believe they will have an important place in treatment of cutaneous T-cell lymphoma in future.