Brodalumab for the treatment of moderate-to-severe plaque-type psoriasis: a real-life, retrospective 24-week experience.

BACKGROUND: Brodalumab was efficacious and safe in moderate-to-severe plaque-type psoriasis in the AMAGINE trials; published reports under real-life conditions are limited. OBJECTIVES: To evaluate the effectiveness and safety of brodalumab in patients with moderate-to-severe plaque-type psoriasis in a real-world setting. METHODS: This observational, retrospective study enrolled adult patients (≥18 years) with moderate-to-severe plaque-type psoriasis who underwent 24 weeks of treatment with brodalumab at 17 Italian dermatological centres. Baseline data included demographics, comorbidities, age of onset and duration of psoriasis and previous treatments. Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA), static PGA of Genitalia, Dermatology Life Quality Index and patient satisfaction were assessed at weeks 0, 4, 12 and 24; adverse events were recorded. RESULTS: Seventy-eight patients (mean age 47.9 years, 71.8% male, average disease duration 16.8 years) were enrolled. A rapid and significant reduction in mean PASI score was observed after 4 weeks of treatment, decreasing further at weeks 12 and 24 (all P < 0.0001 vs. baseline). A higher number of cardiometabolic comorbidities and previous therapies were negatively associated with the achievement of PASI 90 at all assessments. Brodalumab was effective in bio-experienced patients, including those who had failed on anti-interleukin (IL)-17 therapies. Quality of life and patient satisfaction increased significantly during treatment (P < 0.0001 and P < 0.01 vs. baseline, respectively). Treatment was interrupted in 9 (11.5%) patients due to adverse events (n = 4), lack of efficacy (n = 3), lost to follow-up (n = 1) and surgical procedure (n = 1). CONCLUSIONS: Brodalumab is effective and safe in the treatment of moderate-to-severe psoriasis in a real-world setting, including in patients with failure to anti-IL17 therapies.

Creation of a severity index for hidradenitis suppurativa that includes a validated quality-of-life measure: the HIDRAscore.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, debilitating disease with a considerable effect on patient quality of life. Its clinical severity can be measured using different scoring systems; however, few of them include patient-centred parameters. OBJECTIVE: To create a new scoring system for HS that includes a quality-of-life instrument, the HIDRAdisk. METHODS: This post hoc analysis was carried out within the framework of a multicentre, longitudinal, epidemiologic study conducted over 9 months on quality-of-life aspects of HS. The new severity score was created using as reference a question from the Subject Satisfaction Questionnaire (SSQ) concerning the severity of HS as evaluated by the patient. Associated variables were selected using univariable and multivariable logistic regression models. The discriminant capabilities of the final model and of the final score were evaluated by the area under the receiver operating characteristic curve and the Hosmer-Lemeshow test. RESULTS: The study population included 308 patients with HS of any severity grade. According to the results of the regression models, the variables associated with the reference SSQ measure were number of inflammatory nodules, abscesses and draining fistulas; the HIDRAdisk score; and the number of subumbilical lesions. The HIDRAscore is obtained by the sum of the scores associated with the number of these parameters. Possible scores range from 0 to 10. CONCLUSION: The HIDRAscore is a new scoring system for HS severity which, in addition to the clinical evaluation by the physician, includes a validated patient-reported outcome measure, the HIDRAdisk.

Sex-related differences of clinical features in hidradenitis suppurativa: analysis of an Italian-based cohort.

The clinical characteristics associated with hidradenitis suppurativa (HS) severity are poorly understood. In this study, 124 patients with HS from 6 Italian dermatology centres participated in this study. Disease severity was assessed using the Hidradenitis Suppurativa Physician's Global Assessment score (HS-PGA) and Hurley score. The impact of clinical characteristics on disease severity was assessed by logistic regression. Clinical characteristics were similar between men (n = 53) and women (n = 71). Disease severity was also similar; 75% of the patients had Hurley stage II or III disease, and > 60% had moderate, severe or very severe HS as judged by HS-PGA. Lesions were more frequent in the gluteal region in men (32.3% in men vs. 8.7% in women, P < 0.001) and more frequent on the breast in women (16.3% in women vs. 4.6% in men, P = 0.02). Obesity was associated with increased disease severity as measured by HS-PGA (OR: 3.28, 95% CI 1.55-6.95, P < 0.01) and Hurley classification (OR: 3.22, 95% CI 1.34-7.31, P < 0.01). Although severity of HS is similar between the sexes, the localization of lesions is different.

Secukinumab in multi-failure psoriatic patients: the last hope?

Psoriasis is a multi-systemic chronic inflammatory disease that affects about 1.5-3% of the general population, of which almost 20% suffer from a moderate-severe form. Those patients can be treated with a systemic agent and in case of scarce response or contraindications, they may require a biologic therapy, such as tumor necrosis factor or interleukin-12/23 inhibitors. When also these agents fail, clinicians face a true therapeutic challenge. We report a case series of multi-failure 16 patients, successfully treated with secukinumab, a human monoclonal antibody that selectively neutralizes interleukin-17 A and is recently approved for the treatment of plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis.

Oxidative stress and psoriasis: the effect of antitumour necrosis factor-α inhibitor treatment.

BACKGROUND: Psoriasis is a chronic, inflammatory skin condition associated with a high frequency of cardiovascular events. Modifications of plasma lipids, and an increase in the levels of biochemical markers of inflammation and lipid peroxidation have been reported in subjects with psoriasis, suggesting a relationship between psoriasis, inflammation and oxidative damage. OBJECTIVES: To investigate whether modulation of inflammatory activity by tumour necrosis factor-α inhibitors in patients with psoriasis is associated with modification of lipid profiles, oxidative stress and paraoxonase (PON)1 activity. METHODS: The levels of plasma lipids and lipoprotein(a), and the levels of the markers of inflammation and lipid peroxidation were evaluated in subjects with psoriasis (n=23) before and after 24 weeks of treatment with etanercept. In the same subjects plasma total antioxidant capacity and the activity of PON1, an antioxidant and anti-inflammatory enzyme associated with the high-density lipoproteins (HDLs), were investigated. RESULTS: The results showed that clinical improvement in patients with psoriasis treated with etanercept is associated with a reduction in the levels of inflammatory markers [C-reactive protein (CRP)] and lipid peroxidation, and also with increased antioxidant capacity in the serum of patients with psoriasis. These modifications are associated with a significant increase in the activity of PON1. A significant increase in the PON1/CRP ratio has also been observed in patients with psoriasis after treatment. The significant inverse correlation between CRP and PON1 activity suggests a relationship between PON1 activity and inflammation. CONCLUSIONS: Treatment with etanercept is associated with a reduction in lipid peroxidation and an improvement in HDL antioxidant and anti-inflammatory properties.

Doxycycline-isoniazid: a new therapeutic association for recalcitrant acne agminata.

Acne agminata is a rare asymptomatic, inflammatory dermatosis, which affects adolescence and young adults, whose etiopathogenesis is already controversial. Clinically, acne agminata is characterized by red-yellow-brown papular-pustular eruption involving the central face, in particular cheeks, chin, forehead, and eyelids. The authors report a case of a 25-year-old Caucasian man affected by acne agminata treated with doxycycline and isoniazid.

Videocapillaroscopic pattern of alopecia areata before and after diphenylciclopropenone treatment.

Alopecia areata (AA) is an inflammatory skin disease the most effective therapy for which is diphenylcyclopropenone (DPCP). Videodermatoscopy and intra-vital capillaroscopy (IVCP) are two non-invasive techniques that help in the differential diagnosis of alopecias. It is known that, after DPCP therapy, there is a histologically proven significant increase of VEGF in hair follicle keratinocytes and a consequent increase in capillary vessels in the dermis of the same follicles. The aim of our study is to emphasize any clinical and videodermatoscopic-videocapillaroscopic changes after DPCP treatment in 20 patients affected by alopecia areata. Videodermatoscopic images and an intravital videocapillaroscopic analysis were performed at T0, T12 and T24 to emphasize clinical modifications and microscopic changes in vascular pattern before and after DPCP treatment. At T0, videodermatoscopy showed the presence of exclamation point hairs, hair follicles filled with hyperkeratotic plugs (yellow dots), hair follicles containing cadaverized hairs (black dots) and broken hairs. IVCP highlighted a pale scalp, and vessels were not visible. At 24 weeks (T24), videodermatoscopy revealed the disappearance or a statistically significant reduction of AA hallmarks and an increase of number of vellus hairs. Videocapillaroscopy showed a statistically significant increase of new vessels and, where neoangiogenesis were more marked, a major hair regrowth was evident. Our study emphasizes that, after DPCP therapy, neoangiogenesis is detectable by videocapillaroscopy and these new capillaries could be considered an initial positive attempt to compensate capillary loss of T0 alopecia areata images.

Differences in survivin location and Bcl-2 expression in CD30+ lymphoproliferative disorders of the skin compared with systemic anaplastic large cell lymphomas: an immunohistochemical study.

BACKGROUND: Cutaneous CD30+ lymphoproliferative disorders (LPDs) are a spectrum of disease associated with a favourable prognosis. Systemic anaplastic large cell lymphoma (ALCL), although morphologically and phenotypically similar, differs in clinical presentation and has a less favourable biological behaviour. Dysregulation of apoptosis, the process regulating cell population by programmed death, can explain the differences among these disorders. OBJECTIVES: We investigated the expression of two inhibitors of apoptosis, survivin and Bcl-2 protein, in serial skin lesion samples from CD30+ LPDs compared with systemic ALCL. METHODS: Immunohistochemical analysis with antibodies against anaplastic lymphoma kinase (ALK)-1 protein, survivin and Bcl-2 protein was performed in 10 cutaneous CD30+ LPDs (five lymphomatoid papulosis, five ALCL) and 18 systemic ALCLs. Reverse transcription-polymerase chain reaction studies for ALK and ALK/nucleophosmin were also performed. RESULTS: Cutaneous CD30+ LPDs shared a heterogeneous expression of cytoplasmic survivin with all systemic ALCLs, and of Bcl-2 with systemic ALK- ALCLs; however, they differ from systemic ALK- ALCLs because they lack nuclear survivin (P = 0.045), and from systemic ALK+ ALCLs by a higher expression of Bcl-2 (P = 0.045) and a lack of ALK-1. Overall, coexpression of Bcl-2 and nuclear survivin in CD30+ LPDs was associated with a less favourable disease survival. CONCLUSIONS: The different patterns of expression of Bcl-2 and survivin in CD30+ LPDs might have an impact on their different biological and clinical behaviour. Moreover, nuclear localization of survivin, similarly to ALK, may be a useful marker for predicting a systemic form of ALCL with cutaneous presentation.

In vitro activity of posaconazole against clinical isolates of dermatophytes.

A broth macrodilution method following the recommendations established by the National Committee for Clinical Laboratory Standards was used to compare the in vitro activity of posaconazole (PCZ) with that of itraconazole (ITC) against 30 clinical isolates of dermatophytes belonging to six different species. In terms of MICs, PCZ showed an activity equal to that of ITC. MICs of PCZ at which 50% (MIC(50)) and 90% (MIC(90)) of the isolates were inhibited were 0.5 and > 4.0 microg/ml, respectively. The MIC(50) and MIC(90) of ITC were 1.0 and > 4.0 microg/ml, respectively. However, PCZ showed a more potent fungicidal activity than that of ITC against isolates belonging to the genus Microsporum (P = 0.03). PCZ merits further investigation as a potentially useful agent for treatment of dermatophytosis.

Electrophoretic karyotyping and antifungal susceptibility patterns of Candida parapsilosis clinical isolates causing deep and superficial fungal infections.

Forty-six isolates of Candida parapsilosis, each from a single patient, were collected from July 1993 through March 1999 at the University of Ancona Hospitals and Clinics. Twenty-eight strains were isolated from superficial lesioned sites, including skin, nails and other sources while 18 strains were isolated from blood. The isolates were typed by electrophoretic karyotyping (EK) and tested for their susceptibility to fluconazole (FLC), itraconazole (ITC), flucytosine (5-FC), and amphotericin B (AMB). Our data confirmed that EK is a useful technique for DNA typing of isolates of Candida parapsilosis and showed that the source of isolation is not associated with a given DNA type. Although strains belonging to this species of Candida are susceptible to the most common antifungals, including the triazoles, the degree of ITC susceptibility was dose dependent (MIC ranging from 0.25-0.5 microgram/ml) for 98% of the isolates.

Carboxyfullerenes protect human keratinocytes from ultraviolet-B-induced apoptosis.

Carboxyfullerene, a water-soluble carboxylic acid derivative of a fullerene, which acts as a free-radical scavenger, was investigated as a protective agent against ultraviolet-light-induced damage in human keratinocytes. First, we demonstrate that carboxyfullerene is not cytotoxic for these cells. In addition, this compound significantly reduces the ultraviolet-B-induced inhibition of keratinocyte proliferation and protects keratinocytes from apoptosis caused by ultraviolet B irradiation in a time- and dose-dependent fashion. Furthermore, the percentage of cells with depolarized mitochondria is significantly lower in ultraviolet-B-irradiated keratinocytes pretreated with carboxyfullerene than in cells provided with diluent alone. Carboxyfullerene also protects human keratinocytes from apoptosis induced by exposure to deoxy-D-ribose, a sugar that causes cell death through a pathway involving oxidative stress. On the other hand, ultraviolet B downregulates bcl-2 levels in human keratinocytes, and carboxyfullerene fails to prevent this effect. These results suggest that carboxy- fullerene protects human keratinocytes from ultraviolet B damage possibly via a mechanism interfering with the generation of reactive oxygen species from depolarized mitochondria without the involvement of bcl-2.

In vitro activity of terbinafine against clinical isolates of dermatophytes.

A broth macrodilution method following the recommendations established by the National Committee for Clinical Laboratory Standards was employed for testing terbinafine against 20 clinical isolates of dermatophytes belonging to seven species. The minimal inhibitory concentrations resulting in either 80% or 100% inhibition of growth, compared to growth in drug-free control tubes, ranged from

Prevalence and antifungal susceptibility of vaginal yeasts in outpatients attending a gynecological center in Ancona, Italy.

Between February 1993 and May 1994 we studied the prevalence of fungal vulvovaginitis among women attending the Obstetric and Gynecology Clinic of the University of Ancona. Out of the 222 patients, 18 (8.2%) women had symptomatic vaginitis and 24 (10.8%) were carriers. Candida albicans was the species most frequently isolated (44.2%), followed by Torulopsis glabrata (28%) and Saccharomyces cerevisiae (16.2%), from symptomatic and carrier patients. The activity of acid proteinase was determined for C. albicans isolated from both symptomatic and carrier patients. All 13 carriers showed low activity for aspartyl proteinase (score 1+), while 5 of 6 symptomatic patients showed higher activity (score 2+), with a significant difference (p = 0.026). In general, isolates of T. glabrata and S. cerevisiae were less susceptible in vitro to fluconazole than isolates of C. albicans. We did not find any differences in fluconazole MIC results among the C. albicans strains isolated from symptomatic and carrier patients. On the other hand, the fluconazole MICs of T. glabrata and S. cerevisiae isolates showed statistically significant differences between symptomatic and carrier patients (p = 0.009 and p = 0.000, respectively). The differences in proteinase secretion between the isolates from symptomatic and carrier patients suggest a correlation between proteinase production and vaginal candidiasis caused by C. albicans. Torulopsis glabrata, however, was found to be the most common causative agent of vaginitis (7 out 19 episodes), followed by C. albicans (6 out of 19 episodes). Due to the varying patterns of antifungal susceptibility, mainly to fluconazole for the yeast isolates considered in this study, an in vitro susceptibility testing program might be useful for monitoring the outcome of this infection.

Plasma membrane fluidity of keratinocytes of normal and psoriatic skin: a study using fluorescence anisotropy of trimethylammoniumdiphenylhexatriene (TMA-DPH).

The aim of this study was to investigate plasma membrane fluidity in human keratinocytes using fluorescence anisotropy of 1,6-diphenyl-1,3,5-hexatriene (DPH) and its cationic derivative 1-[4-(trimethylamino)-phenyl]-6-phenyl-1,3,5-hexatriene (TMA-DPH). Keratinocytes from normal or psoriatic skin were isolated using trypsin-EDTA or dispase. In keratinocytes isolated from normal skin, TMA-DPH anisotropy values were higher than those observed using DPH; the difference must be related to the different localization of the two probes. In fact, DPH in whole cells localizes in plasma as well as intracellular membranes, yielding an average value of fluidity, while the cationic derivative TMA-DPH resides in the plasma membrane of the whole cells for a sufficient time for anisotropy measurements. Moreover, it has to be considered that plasma membrane is more ordered than intracellular membranes. The kinetics of incorporation of TMA-DPH was similar in keratinocytes isolated using trypsin-EDTA and those isolated using; dispase, however, the fluorescence anisotropy values were lower in keratinocytes isolated with dispase (0.260 +/- 0.01 vs 0.270 +/- 0.01, p = 0.029). This difference is probably related to modifications of lipid-protein interactions after trypsin treatment. Since no damage to plasma membrane after incubation with dispase seems to have been reported, we decided to use this separation procedure to study plasma membrane fluidity in psoriasis, a human pathological condition characterized by excessive cell proliferation and incomplete differentiation. Lower anisotropy values (0.260 +/- 0.01 vs 0.270 +/- 0.01, p = 0.001), indicating an increase in fluidity, were observed in keratinocytes isolated from skin of psoriatic patients than in epidermal cells isolated from normal human skin. We suggest that the measurement of fluorescence anisotropy in living cells is a convenient and useful tool to study membrane fluidity in human keratinocytes isolated from normal and diseased skin. Its application represents a technical advance because plasma membrane fluidity can be measured using very limited amounts of tissue, as obtained from biopsies.

Abnormalities of plasma lipoprotein composition and fluidity in psoriasis.

We have studied the lipoprotein chemical composition and fluidity, using the fluorescence polarization of the probe 1,6-diphenyl-1,3,5-hexatriene (DPH) in two age- and sex-matched groups of subjects (14 healthy normolipidemic children and 15 psoriatic children). The compositional study has shown a significant increase of the percentage content in triacylglycerol and a significant decrease of the apo-protein content in all lipoprotein fractions of psoriatic children compared to the controls. A significant increase of the percentage content in total cholesterol and of the cholesterol/protein ratio has also been observed in low-density lipoproteins (LDL) and in high-density lipoproteins (HDL) of psoriatic children. The compositional changes were associated with alterations of fluidity in LDL and HDL of psoriatic patients. The modifications of lipoprotein composition and fluidity observed in psoriatic patients could be of physiopathological and clinical relevance in relation to the pathogenesis of the disease.

Lipoprotein peroxidation in adult psoriatic patients.

Psoriasis, a chronic inflammatory skin disease characterized by an aberration of lipid metabolism, has been associated with an increased risk for atherosclerosis. Since oxidatively modified lipoproteins are involved in the pathogenesis of atherosclerosis, we investigated the lipid composition and in vitro induced peroxidation of very low density lipoproteins (VLDL) and low density lipoproteins (LDL) from psoriatic patients. 11 male adult psoriatics and 16 male age-matched healthy subjects were studied. Lipid peroxidation of VLDL and LDL was performed by incubation with CuSO4 for 24 h at 37 degrees C. The compositional analysis showed a significant increase in triglycerides and phospholipids, both in VLDL (p < 0.05) and in LDL (p < 0.001) from psoriatic patients, compared with controls. Moreover a significant increase in total cholesterol (TC) (p < 0.01) and apoprotein (P) (p < 0.05) was found in LDL from psoriatics. The levels of thiobarbituric acid reactive substances (TBARS), as a measurement of lipid peroxidation, were significantly higher in Ox-VLDL and in Ox-LDL from psoriatics (p < 0.01) than the corresponding values in controls. Moreover, basal values of TBARS were significantly higher in VLDL and LDL from psoriatic patients than those from controls. In conclusion, the lipoprotein compositional changes associated with the modifications of TBARS before and after Cu2+ treatment of lipoproteins may suggest an increased risk for atherosclerosis in adult psoriatic patients.