Etanercept and efalizumab treatment for high-need psoriasis. Effects and side effects in a prospective cohort study in outpatient clinical practice.

BACKGROUND: Since the beginning of 2005, etanercept and efalizumab are officially registered and reimbursed for the treatment of recalcitrant psoriasis in The Netherlands. OBJECTIVE: The evaluation of the efficacy, safety and adverse events of etanercept and efalizumab treatment in daily practice. METHODS: A prospective cohort study was carried out for patients treated with etanercept or efalizumab between February 2005 and March 2006. RESULTS: Over the past 13 months 45 individuals were treated with etanercept and 17 subjects were treated with efalizumab. The cohort represented a high-need population. At week 12, 82% of the subjects treated with 2 x 50 mg etanercept/week and 71% of the subjects treated with 2 x 25 mg etanercept/week reached a PASI-50. Efficacy of etanercept treatment was comparable to the results of clinical trials. For efalizumab, efficacy in responding patients was also comparable to clinical trial data, but the percentage of dropouts was substantial. During biologic treatment, safety was preserved and mainly mild adverse events were reported. CONCLUSION: Etanercept and efalizumab are effective and safe treatments of psoriasis, even in a high-need population. Etanercept was able to sustain the clinical improvement throughout 24 weeks, whereas efalizumab was not in 47% of subjects.

The effect of topical corticosteroids in combination with alefacept on circulating T-cell subsets in psoriasis.

BACKGROUND: Novel therapies against psoriasis are emerging. Alefacept is such a treatment. It selectively targets the memory effector population of T cells and thereby diminishes the psoriatic plaques. In some cases, however, the use of alefacept as a monotherapy is not sufficient. OBJECTIVE: In the present study we investigate the safety and efficacy of adding topical steroids to alefacept treatment during the initial 4 weeks. METHODS: Peripheral blood was obtained from all patients and the presence of specific T-cell subsets was assessed by flow cytometry. Fourteen patients were included and treated with 15 mg alefacept intramuscularly for a period of 12 weeks. Each of them was randomized to use either betamethasone-dipropionate cream or a vehicle cream during the first 4 weeks of the alefacept course. RESULTS: Additional topical corticosteroid treatment during the first 4 weeks of alefacept treatment does not have a beneficial effect on the clinical efficacy. Marked changes were seen in the absolute cell counts of various of the analysed T-cell subsets in peripheral blood after 12 weeks of alefacept, either with or without additional local steroid application. The CD45RO+, CD8+CD45RO+, CD8+CD161+, CD4+CD25+, CD4+CLA+ and CD8+CLA+ populations showed a statistically significant decrease immediately after the treatment period. Further analysis revealed that the addition of local steroid therapy to alefacept results in marked decreases of all T-cell subsets analysed in this study, in contrast to the addition of the vehiculum only. CONCLUSION: Alefacept selectively targets the CD45RO+ lymphocyte population, as well as some other subpopulations of lymphocytes. This effect is independent of the use of additional topical therapy during the first 4 weeks. The extent of the decrease, on the contrary, is dependent on the use of corticosteroids.

The added therapeutic efficacy and safety of alefacept in combination with other (systemic) anti-psoriatics in refractory psoriasis.

OBJECTIVE: Alefacept is a biologic treatment for psoriasis, with a selective effect on memory effector T cells. Few data are available on the combination of alefacept with either topical or systemic anti-psoriatics. We studied the effect of alefacept combination treatment on clinical disease severity scores and on circulating T-cell subsets. METHODS: Twelve patients with moderate-to-severe psoriasis were included and treated with alefacept for a period of 12 weeks. Patients were allowed to continue the anti-psoriatic therapies they used prior to the study. Severity of disease and expression of T-cell markers CD4, CD8, CD45RA, CD45RO, CD94, CD161, CD25, and CLA were assessed at baseline and after treatment. RESULTS: Seven of 12 included patients used a concomitant systemic therapy: either methotrexate (n = 4), acitretin (n = 2) or cyclosporine (n = 1). PASI reductions in this group after 12 and 24 weeks were 40% and 55%, respectively. Several lymphocyte subsets showed a reduction in circulating numbers. These decreases were independent of the use of an additional systemic psoriasis therapy. CONCLUSIONS: The concomitant use of systemic anti-psoriatic medication in combination with alefacept has a noteworthy impact on efficacy results. No differences in circulating psoriasis-relevant T-cell populations between patients with or without an additional systemic treatment were seen.

Severe pyoderma gangrenosum unresponsive to etanercept and adalimumab.

BACKGROUND: A 74-year-old female with severe and therapy-resistant pyoderma gangrenosum (PG) was treated for more than 40 years with topical antibacterial ointments, topical and systemic corticosteroids, dapsone and azathioprine. Generally, immunosuppression is the mainstay of treatment of PG, but in our patient cyclosporine had to be discontinued because of significant serious side effects. An attempt was made to decrease the amount of steroids, but tapering of the prednisone dose resulted in relapses of PG. OBSERVATION: Off-label use of etanercept resulted in a temporary limited clinical improvement. After 6 months, initial clinical improvement reduced and adalimumab was started. Unfortunately, after 6 months of adalimumab no clinical improvement was seen. Therefore, systemic corticosteroids had to be continued with very good clinical results. CONCLUSION: In concordance with previous results of several other studies, reviews and case reports, we presume that possibly both etanercept and adalimumab could be excellent therapeutic alternatives in the treatment of PG. Unfortunately, the effectiveness of both etanercept and adalimumab were very limited in our case. Literature research revealed no other successful studies on the off-label use of other immunomodulators as an alternative treatment option for PG. However, infliximab or ustekinumab could be alternative treatment options.

Dimethylfumarate for psoriasis: Pronounced effects on lesional T-cell subsets, epidermal proliferation and differentiation, but not on natural killer T cells in immunohistochemical study.

BACKGROUND: T-cell infiltration, epidermal hyperproliferation, and disturbed keratinization are pathologic hallmarks of plaque psoriasis. Oral fumaric acid esters are an effective therapy for psoriasis and are believed to exert their effects mainly through their anti-inflammatory properties. OBJECTIVE: To investigate the differential effects of dimethylfumarate (BG-12; FAG-201) for psoriasis on lesional T-cell subsets, natural killer (NK) T cells, and keratinocyte hyperproliferation and differentiation. STUDY DESIGN: A before-and-after clinical and immunohistochemical study as part of a larger clinical trial. SETTING: Single outpatient clinic. PATIENTS: Six patients with moderate-to-severe psoriasis. INTERVENTION: Dimethylfumarate 720 mg daily for 16 weeks. METHODS: Biopsies were taken from the lesional skin of six psoriatic patients, at baseline and after 16 weeks of treatment with dimethylfumarate. Clinical severity scores were obtained (Psoriasis Area Severity Index [PASI] and psoriasis severity SUM scores). T-cell subsets (CD4+, CD8+, CD45RO+, CD45RA+, CD2+, CD25+), cells expressing NK receptors (CD94, CD161), an epidermal proliferation marker (Ki67), and a keratinization marker (K10) were immunohistochemically stained and, together with 'epidermal thickness,' quantified using image analysis. RESULTS: At week 16, the mean PASI and SUM scores were reduced by 55% (p < 0.01) and 49% (p < 0.01), respectively. In line with these results, epidermal hyperproliferation, keratinocyte differentiation, and epidermal thickness significantly improved. In the dermis and the epidermis, the relevant T-cell subsets significantly declined. However, in both the lesional psoriatic dermis and epidermis, cells expressing NK receptors (CD94 and CD161) persisted after 16 weeks of treatment. CONCLUSIONS: Dimethylfumarate is an effective therapy for moderate-to-severe plaque psoriasis. The drug may act by reducing lesional T-cell subsets and normalizing epidermal hyperproliferation and keratinization, but does not reduce NKT cells.