Ustekinumab treatment for moderate-to-severe plaque psoriasis: eight-year real-life experience.

Background: Limited information is available from real-life studies evaluating the long-term efficacy and drug retention of ustekinumab.Research design and methods: Data from 378 patients with moderate-severe psoriasis were retrospectively analyzed. Over 8 years, disease severity and treatment response were evaluated using the PASI score. Predictors of PASI response were evaluated by logistic regression. Ustekinumab retention rate was calculated by the Kaplan-Meier method.Results: Over the 8 years, >80% of patients achieved a PASI score of <3 and PASI 75, 90 and 100 response was achieved in 76.2%, 61.9% and 57.1% of patients, respectively. Predictor variables for improved PASI response (after 2 years) were HLA-C*06-POS patients, female gender and BMI <30 Kg/M2. The 2-year retention rate was 81% and 59% after 8 years with mean retention rate of 5.4 years. Improved retention rate was observed in patients positive for the HLA-C*06 allele (3.7 vs. 2.5 years, p = 0.005) and female gender (3.7 vs. 3.3 years, p = 0.06), with no significant difference observed in other patient groups. Ustekinumab was generally well tolerated without evidence of cumulative toxicity or organ toxicity.Conclusion: The long-term use of ustekinumab was observed to be effective and safe in patients with moderate-severe chronic psoriasis in a real world-setting.

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.

Psoriasis Area and Severity Index response in moderate-severe psoriatic patients switched to adalimumab: results from the OPPSA study.

BACKGROUND: Few studies have compared the efficacy of switching to adalimumab in the real-life setting in plaque psoriasis patients. OBJECTIVE: To evaluate the effect of adalimumab in psoriasis patients previously treated with other biologics. METHODS: In this multicentre study, psoriasis patients (N = 262) treated with an anti-TNF-alpha agent, ustekinumab or naïve to biologics then switched to adalimumab were included. Disease severity was assessed by the Psoriasis Area and Severity Index (PASI) at baseline and after 3, 6, 12, 24 and 36 months. The association between clinical risk factors and achievement of PASI response was evaluated by logistic regression. RESULTS: Adalimumab treatment resulted in a decrease in PASI (15.1 ± 6.2 at baseline vs. 2.7 ± 4.8 at 6 months, P < 0.0001), regardless of previous biologic treatment. Furthermore, adalimumab allowed 92.5%, 79% and 56% of patients to achieve PASI response (PASI 50, 75 and 90, respectively) and complete remission (PASI 100 response) in 48.4% of patients, by 6 months and maintained over 3 years, independent of prior biologic treatment. The absence of metabolic syndrome, dyslipidemia, hypertension and lower PASI and lower age at baseline was associated with achievement of PASI response at 3, 6 and 12 months, whereas at later time points (24 and 36 months), PASI 90 and PASI 100 response was associated with diagnosis of psoriasis/psoriatic arthritis. CONCLUSION: Adalimumab was effective at reducing PASI score over 3 years, irrespective of whether patients were biologic naïve or previously treated with a TNF-alpha or IL-12/23 inhibitor.

Effect of biophysical therapy on articular pain in a primary care setting compared to ibuprofen and placebo: a randomized controlled trial.

Articular pain is one of the most frequent complaints practitioners face in their daily work. With an aging population, many patients have multiple comorbidities that are associated with the presence of chronic diseases, while others experience allergies, side effects or do not respond to standard medications or procedures. Therefore, there is an urgent need for new effective and safe strategies to manage articular pain, especially in its chronic manifestations. This randomized controlled trial was designed to assess the efficacy of a single therapy session using a biophysical procedure matched with a common non-steroidal anti-inflammatory drug (ibuprofen) and placebo. Biophysical therapy was performed using a Med Select 729 device. One hundred fifty patients (mean age 56±15.6 years) diagnosed with acute or chronic articular pain at different locations were randomized into 3 groups and the Numeric Pain Rating Score (NPRS) was used to measure pain at baseline, after one week, one month, and three months. While no difference in NPRS was observed at baseline among the 3 groups, a statistically significant difference was observed at all subsequent time points, respectively, after one week (p less than 0.05), one month (p less than 0.001), and three months (p less than 0.01), for both ibuprofen and biophysical groups vs placebo. Biophysical treatment of articular pain was shown to be as effective as a conventional non-steroidal anti-inflammatory treatment over a period of 3 months compared to placebo and could, therefore, represent an integrative, safe and long-lasting therapy to be considered for the management of acute and particularly chronic articular pain in current medical practice.

Clinical, ultrasound, and videodermatoscopy monitoring of psoriatic patients following biological treatment.

BACKGROUND AND PURPOSE: Effective non-invasive techniques to monitor plaque psoriasis progression and treatment are desirable. The aim of the study was to evaluate changes in vascular pattern using videodermatoscopy (VD) and in skin thickness by ultrasound (US), along with clinical observation, during treatment with biologicals. METHODS: Forty-two patients with moderate-to-severe plaque psoriasis treated with adalimumab, etanercept, or ustekinumab were evaluated. Following the identification of a 'target' plaque at baseline, lesion changes were monitored at 15, 30 and 60 days by clinical observation using a Target Lesion Score (TLS), and by VD and US. RESULTS: After 60 days, a significant improvement in all three parameters was observed. In adalimumab-treated patients mean values of TLS, VD, and US were reduced by 83.9%, 73.5%, and 90%, respectively; in etanercept-treated patients by 67.9%, 49.7%, and 79.3%; in ustekinumab-treated patients by 80.9%, 66.4%, and 80.1%. Skin thickness was the first parameter to improve. Vascular improvement was slower compared to clinical and US responses. CONCLUSION: VD and US may be useful to monitor psoriasis treatment. Further investigations are warranted to assess if the persistence of an altered vascular pattern despite clinical and US normalization, as observed in 22% of patients, may influence disease progression and/or correlate with rate and severity degree of relapse.

Pioglitazone Randomised Italian Study on Metabolic Syndrome (PRISMA): effect of pioglitazone with metformin on HDL-C levels in Type 2 diabetic patients.

BACKGROUND: Previous evidence indicates that pioglitazone may improve dyslipidemia in patients with Type 2 diabetes mellitus (T2DM). AIM: The primary objective of this study was to evaluate the effect of either pioglitazone or placebo with metformin on levels of serum HDL cholesterol (HDL-C) in patients with T2DM. A secondary objective evaluated changes in metabolic syndrome (MS)-specific parameters. SUBJECTS AND METHODS: This multicenter, double-blind, randomized study was performed in patients with T2DM treated with metformin and hemoglobin A1c (HbA1c) levels between 6-8%, central obesity and reduced HDL-C. MS was evaluated from global changes in parameter values and expressed as a single factorial score following multivariate analysis of each parameter. 213 patients (110 in the pioglitazone group and 103 in the placebo group) were available for intention-to-treat analysis. RESULTS: Pioglitazone-treated patients showed a significant increase in HDL-C compared to placebo group (6.3 mg/dl vs 3.0 mg/dl; p<0.01) in addition to a greater reduction in the extent of MS (-13.2 vs -4.9; p=0.0055). Upon study completion, patients treated with pioglitazone had lower levels of HbA1c (6.41±0.65 vs 6.96±0.74%; p<0.001) and homeostasis model assessment-insulin resistance (HOMA-IR) (2.88±1.95 vs 4.68±3.63; p=0.013) and a reduction of the atherogenic LDL subfraction (pattern B) (-5.7%). CONCLUSIONS: The beneficial effects observed in pioglitazone-treated patients in the present study, (i.e. the increase in HDL-C and the reduction of insulin resistance and atherogenic LDL subfractions), support findings from the PROactive trial, where pioglitazone showed pleiotropic effects and reduced death, fatal myocardial infarction (MI) and non-fatal MI in T2DM patients with MS. Furthermore, medication used in this study showed good tolerability.

Effect of pioglitazone on cardiac sympathovagal modulation in patients with type 2 diabetes.

This study aims to examine the effect of pioglitazone on potential progression of autonomic damage in addition to changes in control of cardiovascular function in patients with type 2 diabetes (T2DM). Thirty patients with T2DM and 32 healthy subjects participated in the study. Sympathovagal activity, assessed by power spectral analysis (PSA) of R-R intervals variability, and blood pressure (BP) were studied during clinostatism and orthostatism in controls and patients. We have assessed blood pressure control by 24-hour monitoring of ambulatory blood pressure. Patients were treated with pioglitazone (30 mg/day) for 6 months, and then re-evaluated by PSA for heart rate variability (HRV). Reduced levels of HbA1c (P < 0.0001) and urinary albumin (P = 0.008) were observed in pioglitazone-treated patients compared to untreated baseline levels. Arterial BP remained unchanged following pioglitazone treatment. T2DM patients had reduced HRV (low-frequency power; LF; P < 0.0001 and LF/HF; LF/HF; P < 0.0001) at baseline (clinostatism) compared to controls. Baseline clinostatic differences between groups persisted after pioglitazone treatment and no effect of treatment on basal HRV variables was observed. In controls, HF decreased and LF and LF/HF ratio increased in the orthostatic position. A similar effect for HF was observed in patients, but LF and LF/HF did not increase. The normal difference between HF-power in clinostatism versus orthostatism observed for controls (P < 0.0001) was restored in patients following pioglitazone treatment (P = 0.028). A significant decrease from lying to standing position in orthostatic LF-power (P < 0.0001) and LF/HF (P < 0.0001) was also observed between patients and controls. Although no differences in autonomic control of HRV were observed between controls and patients with T2DM, significant differences were observed in sympathovagal balance following either clinostatic or orthostatic challenge. These findings provide initial evidence of a potential additional benefit afforded by pioglitazone for the improvement of cardiac sympathovagal balance in T2DM.

Mucoactive drugs.

Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action.

Bioavailability of Sandimmun® versus Sandimmun Neoral®: a meta-analysis of published studies.

For the past 25 years, cyclosporine A (CyA) has played a pivotal role in transplant immunosuppressant therapy. From the availability of the 2 primary marketed formulations (Sandimmun® and Sandimmun Neoral®, Novartis), confusion has existed with regard to whether these two formulations are bioequivalent. Due to the underlying clinical relevance of this information, we therefore conducted a meta-analysis of all available comparative pharmacokinetic studies to assess whether the two different CyA formulations, Sandimmun® and Sandimmun Neoral®, can be considered bioequivalent. All clinical studies that compared the bioavailability of the 2 formulations in organ transplant recipients were considered for analysis. We searched computerised databases (Embase/Excerpta Medica and Medline/PubMed) from their inception to May 2010. Only studies with AUC values determined at 12 hours were considered for analysis. Relative bioavailability was calculated with 90 percent confidence intervals (CI) for Sandimmun® (test substance) versus Sandimmun Neoral® (reference substance) according to Schuirmann?s Two One-Sided Tests Procedure and the Classical Shortest CI. Homogeneity of data was tested using the Χ(2) test. Fifteen studies were considered for meta-analysis and none of these studies reported AUC values in the 80-125 percent range required for the bioequivalence of two formulations. The overall bioavailability for Sandimmun® versus the microemulsion formulation Sandimmun Neoral® was 76 percent, with upper CI limits lower than 80 percent in some cases. Mean AUC values for Sandimmun® were significantly lower than those for Sandimmun Neoral® (p<0.01). This study demonstrates that the 2 main cyclosporine formulations, Sandimmun® and Sandimmun Neoral®, cannot be considered bioequivalent.

Endothelial progenitor cells and colony-forming units in rheumatoid arthritis: association with clinical characteristics.

OBJECTIVE: To compare levels of a range of endothelial progenitor cells (EPCs) and endothelial colony-forming units (CFUs) in control participants and RA patients, in addition to verifying whether levels of EPCs or CFUs are associated with clinical characteristics in RA patients. METHODS: Peripheral blood mononuclear cells (PBMCs) from 36 RA patients and 30 control participants were analysed by flow cytometry for EPCs defined by the expression of CD34/CD133, CD34/CD117, CD34/CD31, CD34/KDR and CD34/CD133/KDR. Endothelial cell colonies derived from culture of PBMCs were also assessed by CFU assay. RESULTS: No differences in levels of EPCs were observed in RA patients compared with controls. However, levels of EPCs were negatively associated with prognostic markers of poor disease status, but not cardiovascular (CV)-related risk factors. Furthermore, the majority of EPCs examined were negatively correlated with levels of RF. In contrast, CFU number was significantly reduced in RA patients compared with controls and was negatively associated with CV risk factors only. CONCLUSION: These findings indicate that more informative than comparing changes in absolute levels of EPCs, the examination of their relationship with clinical characteristics of RA patients can reveal significant associations, which may provide important clinical insights.

Generalised reduction of putative endothelial progenitors and CXCR4-positive peripheral blood cells in type 2 diabetes.

AIMS/HYPOTHESIS: In patients with type 2 diabetes, reduced levels of circulating endothelial progenitor cells have been reported and these have been correlated with disease severity. In this study, we examined a panel of markers widely used to identify progenitor and/or stem cells, and determined their association with disease severity in diabetic patients. Since expression of chemokine (C-X-C motif) receptor 4 (CXCR4) has been associated with mobilisation and recruitment of progenitor cells, CXCR4 expression was also analysed. METHODS: Peripheral blood mononuclear cells (PBMCs) from 98 patients with type 2 diabetes and 39 control individuals were analysed by flow cytometry for surface marker expression. RESULTS: Cells expressing different combinations of progenitor and/or stem cell markers were severely reduced in PBMCs of diabetic patients compared with those of control participants. Moreover, a number of these putative progenitor cell populations were negatively associated with disease severity. Reduced expression of CXCR4 and CD34/CXCR4-positive cells was also observed in diabetic patients. PBMCs expressing CXCR4 positively correlated with levels of progenitor cells in control participants but not in diabetic patients. Levels of putative progenitor and CXCR4-positive cells were further decreased in patients with diabetic complications, including cardiovascular and microvascular diseases. CONCLUSIONS/INTERPRETATION: A generalised decrease in a range of progenitor cell populations was observed in type 2 diabetic patients. This reduction was also negatively associated with disease severity.

Expression of constitutive but not inducible cyclooxygenase maintains articular perfusion in the rat knee.

Experiments were performed in the normal rat knee joint to investigate the role of different isoforms of cyclooxygenase (COX) in the regulation of basal joint blood flow. Laser Doppler imaging (LDI) was used to measure articular perfusion, and reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of COX-1 and COX-2 mRNA in joint tissue. Intravenous infusion of indomethacin (a non-selective inhibitor of COX; 0.34 nmol min(-1)) over 40 min produced a time dependent increase in articular vascular resistance (maximum 22.5 % at 40 min; P < 0.0001, one-way ANOVA) whereas vehicle over a similar time period had no effect in a control group. An equimolar concentration of a highly selective inhibitor for COX-2, SC-236, was administered in a further group of rats but this did not increase articular vascular resistance. While there was no significant difference between the response to vehicle and SC-236 (two-way ANOVA; P = 0.686, n = 6) the response to indomethacin was significantly greater than vehicle or SC-236 (two-way Anova; P < 0.0001, n = 6). COX-1, but not COX-2, was detectable by RT-PCR in all joint tissue samples examined (n = 4). The results of this study indicate that prostaglandins (PGs) play an important role in the maintenance of basal perfusion in the rat knee joint, with COX-1 being the physiologically relevant isoform. Experimental Physiology (2001) 86.2, 191-197.

Metacarpophalangeal joints in rheumatoid arthritis: laser Doppler imaging--initial experience.

Laser Doppler imaging is a noninvasive method yielding a spatial perfusion map. With use of a near-infrared laser, elevated perfusion associated with the metacarpophalangeal joints was detectable in patients with active rheumatoid arthritis. Findings at laser Doppler imaging correlated with pain scores and synovitis detected at ultrasonography, whereas the power Doppler sign (red pixels inside the active green box) did not. Laser Doppler imaging has the potential to help assess soft-tissue inflammation.