Effectiveness of guselkumab in patients with facial and/or genital psoriasis: Interim analysis results at Week 12 from the GULLIVER study.

BACKGROUND: Facial (FP) and genital psoriasis (GP) significantly affect patients' quality of life. Despite the advances in treatments, limited data on efficacy and safety are available on these difficult-to-treat areas. Guselkumab is an interleukin (IL)-23 inhibitor which has been proven effective in treating patients with moderate-to-severe plaque psoriasis. OBJECTIVES: The aim of this interim analysis was to report the efficacy and safety of guselkumab in the treatment of patients with FP and/or GP. MATERIALS AND METHODS: GULLIVER is a 52-week Italian observational study to evaluate the effectiveness and safety of guselkumab in a real-life setting in patients with FP and/or GP. Adult patients with facial and/or genital moderate-to-severe psoriasis (sPGA score ≥ 3) were included. The primary endpoint of this analysis was the percentage of patients achieving a facial or genital sPGA score of 0 (clear) or 1 (almost clear), at Week 12. The change in the score of the facial or genital sPGA components in patients with a score ≥3 for each sPGA component was assessed. PASI score in patients with a baseline PASI above or below 10 was evaluated. RESULTS: Overall, 351 patients were included in the study; 83.3% of FP and 76.5% of GP patients achieved the primary endpoint. Similar response rates were observed for the facial or genital sPGA components in patients with a baseline facial or genital sPGA score ≥3 in each component. Among patients with a baseline PASI score >10, mean PASI score improved from 19.0 (SD 8.3) to 2.2 (SD 4.8). Forty-four AEs were observed in 32 patients; two mild and transient AEs (fatigue and nausea) were considered treatment related. No SAEs were observed. CONCLUSIONS: Guselkumab, showing to be effective and safe in treating FP and GP, may be a valid therapeutic option for patients with psoriasis localized in these difficult-to-treat areas.

Clinical remission of psoriatic arthritis in patients receiving continuous biological therapies for 1 year: the experience of an outpatient dermatological clinic for psoriasis.

BACKGROUND: The data in the literature concerning the frequency of remission of inflammatory arthritis in patients with psoriatic arthritis (PsA) are limited and conflicting. AIM: To evaluate the frequency of clinical remission in inflammatory arthritis in a cohort of patients with PsA receiving continuous treatment (1 year) with tumour necrosis factor-α inhibitors or ustekinumab, as well as the clinical covariates affecting remission. METHODS: We retrospectively evaluated 74 patients with PsA attending our psoriasis outpatient dermatology clinic. Remission of PsA was defined as documented absence of clinical signs related to arthritis (no tender or swollen joints), enthesitis or dactylitis. Patients were examined every 3 months for 1 year. RESULTS: At 1 year > 40% of patients had clinical remission of inflammatory arthritis. Predictors of remission were absence of fibromyalgia (FM) at baseline and having < 11 tender joints. CONCLUSIONS: Clinical remission of inflammatory arthritis can be obtained in a significant proportion of patients by continuous treatment with biological drugs. A large number of tender joints and the presence of FM can make remission less likely.

Immunologic biomarkers for clinical and therapeutic management of psoriasis.

BACKGROUND: The therapeutic management of psoriasis includes conventional treatments as well as the new generation of highly effective TNF-α inhibitors. However, psoriasis has proven to be a complex therapeutic challenge and treatment failures are not uncommon. Thus, laboratory biomarkers of disease progression/therapeutic efficacy may greatly help in the clinical management of psoriasis. AIMS: To identify laboratory biomarkers for clinical management and therapeutic monitoring of psoriasis. METHODS: An observational study performed on 59 patients, presenting moderate to severe psoriasis, undergoing treatment with anti-TNF-α agents (etanercept, adalimumab, and infliximab). Soluble and cellular immune/inflammatory parameters were assessed at baseline and after 12 and 24 weeks of treatment. RESULTS: Clinical efficacy was achieved in 88% of the subjects at 12 weeks, reaching 90% after 24 weeks. IL-6 and IL-22, which were elevated at baseline, were significantly reduced, in association with a significant decrease of CLA+ T cells and an increase of Treg lymphocytes. T, B, and NK cell subsets and T cell response to recall antigens did not show any evidence of immune suppression. CONCLUSIONS: Immune/inflammatory parameters including IL-6 and IL-22, CLA+ T cells, and Treg lymphocytes may prove to be valuable laboratory tools for the clinical and therapeutic monitoring of psoriasis.

The diagnosis of early psoriatic arthritis in an outpatient dermatological centre for psoriasis.

BACKGROUND: Most of the data currently available on early psoriatic arthritis (EPsA) derive from studies performed in rheumatological settings. However, in recent years, there has been an increase in the amount of data from dermatologic centres. OBJECTIVES: To describe the prevalence, clinical, laboratory and imaging characteristics of psoriatic patients with EPsA seen at a dermatological outpatient psoriasis centre. METHODS: From January 2007 to May 2010, all patients with psoriasis who visited the psoriasis centre were asked about inflammatory joint involvement. A diagnosis of psoriatic arthritis was made on the basis of clinical, laboratory and imaging studies. The patients were diagnosed with early PsA (EPsA) if their inflammatory articular symptoms had been present for ≤ 1 year. RESULTS: We diagnosed EPsA in 33 patients. Joint involvement was polyarticular (>5 joints involved) in 20 patients (60.6%) and oligoarticular (≤5 joints involved) in the remaining 13 patients. Quality of life due to skin involvement and the degree of functional impairment due to joint inflammation were only mildly affected, as measured by DLQI and HAQ, respectively. A direct correlation between the number of tender joints (ACR 68) and HAQ was found (r = 0.36; P = 0.04). Imaging studies showed that in spite of the absence of radiologic findings of peripheral joint damage, ultrasonography and contrast enhanced ultrasonography showed signs of articular inflammation in all patients. CONCLUSIONS: A diagnosis of EPsA can be correctly performed in a dermatologic outpatient facility. To do so, a close collaboration among dermatologists, rheumatologists and radiologists is necessary.

High prevalence of latent tuberculosis infection in autoimmune disorders such as psoriasis and in chronic respiratory diseases, including lung cancer.

The early diagnosis and treatment of individuals harboring M. tuberculosis is key to ensuring the effectiveness of health programs aimed at the elimination of tuberculosis (TB). Monitoring for TB also has other important health care implications for the related immune pathology caused by the chronic inflammatory response to M. tuberculosis. Moreover, the recent introduction of biologic therapies for the treatment of several immune-mediated inflammatory diseases has shown unexpected high frequencies of reactivation of latent TB. The present cross-sectional study is aimed at estimating the prevalence of latent tuberculosis infection (LTBI) in different groups of subjects, either undergoing a routine program of screening for TB or a clinical monitoring of autoimmune or lung disorders, by analyzing their immune response in vitro to a pool of different M. tuberculosis antigens through an IFN-gamma-release assay (IGRA). We consecutively tested 1,644 subjects including health care workers (931), healthy immigrants from different countries (93), patients with a diagnosis of psoriasis (405), patients with lung inflammatory disease (60) or lung neoplasia (32) and a group of HIV-1 infected Italian subjects (120). The prevalence of IGRAs positive responses among health care workers was 8.9 percent. In comparison, significantly higher frequencies were found in healthy immigrant subjects (33.3%), similar to those found in inflammatory broncho-pneumopathies (34.5%) or lung cancer (29.6%). Interestingly, an unexpected high prevalence was also found in patients affected by psoriasis (18.0%), while HIV-infected subjects had values comparable to those of health care workers (10.8%). An age cut-off was determined and applied for each group by receiver operating characteristic (ROC) curves in order to perform the statistical analysis among age-comparable groups. Multivariate analysis showed that the age and clinical conditions such as having a diagnosis of psoriasis or a lung inflammatory disease were independent risk factors for developing an IGRA positive response. This study highlights an unprecedented high prevalence of IGRA positive responses among patients affected by psoriasis and emphasizes the need for a preliminary assessment of LTBI before the administration of any biologic therapy based on cytokine antagonists such as anti-TNF-alpha. Moreover, screening for LTBI should be routinely performed in the presence of a chronic pulmonary disease.

Pulmonary sarcoidosis in a patient with psoriatic arthritis during infliximab therapy.

The occurrence of sarcoidosis during anti-TNF-alpha therapy has occasionally been published. We report the case of a psoriasis patient who developed pulmonary sarcoidosis during a cycle of therapy with infliximab.

Effectiveness of etanercept biosimilar SB4 in maintaining low disease activity in patients with psoriatic arthritis switched from etanercept originator: an open-label one year study.

Background: Currently, there are no studies specifically aimed at investigating the effectiveness of etanercept biosimilar SB4 in psoriatic arthritis (PsA).Objectives: Our primary objective was to verify the ability of SB4 to maintain low disease activity in patients switching from reference etanercept to SB4 after 1 year of treatment with this last drug.Methods: Eighty-seven PsA patients with low disease activity at baseline measured by using the clinical Disease Activity Index for Psoriatic Arthritis ≤ 13 (cDAPSA; range 0-154) were prospectively evaluated after 6 and 12 months when switching from the reference etanercept to SB4.Results: One year after switching from the reference etanercept to SB4, 76 (87.3%) out of 87 patients maintained a cDAPSA ≤ 13.Conclusions: SB4 was effective in maintaining a state of low disease activity in the majority of patients switched from the reference etanercept. However, the proportion of patients (11 subjects) who failed to maintain a state of low disease activity at the end of the study was statistically significant. Loss of effectiveness in the above subjects was mainly due to subjective evaluations given by the patients, rather than an objectifiable exacerbation of disease.

[Evidence-based guidelines and nephrological clinical practice: the GRADE system for rating of evidence]. / Applicabilità delle Linee Guida basate sull'evidenza e alla comune pratica clinica: il sistema GRADE.

It has become widely accepted that decision-making should be based on the best available evidence. The preparation of evidence-based guidelines in the interest of improving long-term outcomes has been a challenging task for many societies. Although nephrology is a relatively young medical discipline and therefore presumably well-disposed towards evidence-based decision making, many problems exist and evidence-based approaches to guidelines have also been widely criticized. One key issue has been the availability of only few and suboptimal randomized trials in this discipline. Considerable variation in the grading systems used to assess existing evidence in nephrology guidelines highlights the need for a better tool. Tools that rigidly assess existing evidence need to also explore the applicability to current practice. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system, developed and implemented in 2004 by the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines panel, is the most advanced tool in this direction.

Clinical outcome measures of psoriasis.

Several tools have been introduced in clinical trials to quantify the severity and the response to a given therapeutic regimen of both psoriasis and psoriatic arthritis. Each method present specific advantages and limitations. Here we will discuss some of the most popular clinical outcome measures of both psoriasis (Psoriasis Severity Index, Physician Global Assessment, National Psoriasis Fundation-Psoriasis Score, Dermatology Life Quality Index) and psoriatic arthritis (American College Rheumatology response criteria, Psoriatic Arthritis Response Criteria).

Angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists for preventing the progression of diabetic kidney disease.

BACKGROUND: Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor antagonists (AIIRA) are considered to be equally effective for patients with diabetic kidney disease (DKD), but renal and not mortality outcomes have usually been considered. OBJECTIVES: To evaluate the benefits and harms ACEi and AIIRA in patients with DKD. SEARCH STRATEGY: We searched MEDLINE (1966 to December 2005), EMBASE (1980 to December 2005), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library issue 4 2005) and contacted known investigators. SELECTION CRITERIA: Studies comparing ACEi or AIIRA with placebo or each other in patients with DKD were included. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. Statistical analyses were performed using the random effects model and results expressed as relative risk (RR) with 95% confidence intervals (CI). Heterogeneity among studies was explored using the Cochran Q statistic and the I(2) test, subgroup analyses and random effects metaregression. MAIN RESULTS: Fifty studies (13,215 patients) were identified. Thirty eight compared ACEi with placebo, five compared AIIRA with placebo and seven compared ACEi and AIIRA directly. There was no significant difference in the risk of all-cause mortality for ACEi versus placebo (RR 0.91, 95% CI 0.71 to 1.17) and AIIRA versus placebo (RR 0.99, 95% CI 0.85 to 1.17). A subgroup analysis of studies using full-dose ACEi versus studies using half or less than half the maximum tolerable dose of ACEi showed a significant reduction in the risk of all-cause mortality with the use of full-dose ACEi (RR 0.78, 95% CI 0.61 to 0.98). Baseline mortality rates were similar in the ACEi and AIIRA studies. The effects of ACEi and AIIRA on renal outcomes (ESKD, doubling of creatinine, prevention of progression of micro- to macroalbuminuria, remission of micro- to normoalbuminuria) were similarly beneficial. Reliable estimates of effect of ACEi versus AIIRA could not be obtained from the three studies in which they were compared directly because of their small sample size. AUTHORS' CONCLUSIONS: Although the survival benefits of ACEi are known for patients with DKD, the relative effects on survival of ACEi with AIIRA are unknown due to the lack of adequate direct comparison studies. In placebo controlled studies, only ACEi (at the maximum tolerable dose, but not lower so-called renal doses) were found to significantly reduce the risk of all-cause mortality. Renal and toxicity profiles of these two classes of agents were not significantly different.

Antimicrobial agents and catheter-related interventions to prevent peritonitis in peritoneal dialysis: Using evidence in the context of clinical practice.

BACKGROUND: Peritonitis still represents a common and major complication of peritoneal dialysis. The broader adoption of several strategies, including antimicrobial and catheter related interventions, has been advocated to prevent or reduce the risk of peritonitis in peritoneal dialysis. METHODS: In this article we start with the presentation of a clinical case where concern exists about the strategies for preventing peritoneal dialysis peritonitis. We then look at the available evidence in the form of systematic reviews of randomized trials and individual randomized trials of interventions to prevent peritonitis in peritoneal dialysis. A summary of the evidence is provided and then put in context with the clinical case scenario. RESULTS: Nineteen eligible trials (1949 patients) of antimicrobial agents and 37 (2822 patients) of catheter related interventions to prevent peritonitis in peritoneal dialysis were identified. Nasal mupirocin compared with placebo significantly reduced the exit-site and tunnel infection rate (1 trial, 2716 patient months, RR 0.58, 95% CI 0.40 to 0.85) but not peritonitis rate (1 trial, 2716 patient months, RR 0.84, 95% CI 0.44 to 1.60). As for antimicrobial strategies, perioperative intravenous antibiotics compared with no treatment significantly reduced the risk of early peritonitis (4 trials, 335 patients, RR 0.35, 95% CI 0.15 to 0.80) but not exit site and tunnel infection (3 trials, 114 patients, RR 0.32, 95% CI 0.02 to 4.81). As for catheter related strategies, Y-set and twin-bag systems were superior to conventional spike systems (7 trials, 485 patients, RR 0.64, 95% CI 0.53 to 0.77) and no other catheter-related intervention was demonstrated to prevent peritonitis in PD. CONCLUSIONS: Evidence exists to support the use of perioperative intravenous antibiotic prophylaxis at the time of catheter placement, the twin-bag and Y-set system, as well as prophylaxis with mupirocin in Staphylococcus aureus nasal carriers. Despite lack of evidence, several other agents are used and recommended in major international guidelines, which is reasonable but requires further investigation.

GangliosideGM1 expression during human spinal cord and neural crest development.

GangliosideGM1 represents a widespread component of the neural cell plasma membranes. Cholera toxin-B subunit binds selectively to GM1. Human spinal cords at post-conception (PC) weeks 6 to 11 were examined and early GM1 expression shown on the cell plasma membrane in the developing grey matter at PC week 6. GM1 was demonstrated also in the marginal layer (white matter); on neural crest derivative plasma membrane, i.e. dorsal root (DRG) and sympathetic ganglia; along emerging fibres from DRG and neurite terminals innervating skeletal muscle. GangliosideGM1 is highly expressed in spinal cord primary cultures and is a stringent neural cell marker. GangliosideGM1 represents an early marker of neural differentiation in both spinal cord and neural crest derivatives.

Immunomagnetic isolation of human developing motor neurons.

Human motor neuron (MN) isolation provides a critical tool to study neurophysiological properties and the effects of molecules of clinical relevance on isolated neurons. We developed an immunomagnetic separation technique based on specific MN antigen recognition for nerve growth factor receptor (p75-NGFR). We cultured an average of 250,000 cells from the anterior horns of a single cord (four specimens at postconception Weeks 6.0, 7.2, 8.0, and 8.3). At day 7 in vitro (DIV), choline acetyltransferase (ChAT) and/or p75-NGFR-expressing cells (MNs) represented 72 +/- 2% of the total growing cells. MNs survived for at least 4 weeks in biochemically defined medium. The immunomagnetic separation method has been demonstrated to be effective, reproducible, and quantitative for separation of MNs.

Cytokines in the sera of patients with pemphigus vulgaris: interleukin-6 and tumour necrosis factor-alpha levels are significantly increased as compared to healthy subjects and correlate with disease activity.

Cytokine serum levels, when detectable, are currently measured in many disease states, both to evaluate a possible pathogenetic involvement of such molecules and for clinical purposes. No data are currently available on the cytokine levels in the sera of patients with pemphigus vulgaris (PV), a rare bullous disease of autoimmune origin. This study presents data concerning the levels of 13 different cytokines assayed in the sera of 25 patients affected with PV as compared with 20 healthy subjects using high sensitivity ELISA kits. Of the 13 molecules analyzed, no differences in the levels of most cytokines were observed between pemphigus and control sera, with the exception of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Serum TNF-alpha and IL-6 levels were found to be significantly higher in PV patients than in normal controls (p < 0.001). Furthermore, the levels of the two cytokines decreased after one month of corticosteroid therapy. A significant correlation was found between the serum levels of both TNF-alpha and IL-6 and the number of lesions for each patient (p < 0.001). The data presented support an involvement of at least IL-6 and TNF-alpha in the biological modifications associated with PV manifestations.

Recognition and treatment of psoriasis. Special considerations in elderly patients.

Psoriasis is a chronic dermatological disorder that affects 1 to 2% of the general population. Although its aetiology is still unknown, the importance of genetic factors has been confirmed by many studies, mainly in young individuals. With respect to clinical features, plaque-type psoriasis (localised or generalised) is the most common form. At present, there is no cure for psoriasis and the available treatments can only temporarily clear the skin manifestations. The choice of treatment regimen for psoriasis is based on the severity of the disease, the patient's gender, age, treatment history and level of compliance, and the physician's personal experience. All therapies for psoriasis have different and potentially toxic effects. Therefore, a good knowledge of their relative and absolute contraindications, adverse effects and interactions with other drugs is mandatory. The elderly represent a significant proportion of patients with psoriasis because its prevalence increases with age. Physicians, particularly general practitioners, dermatologists and gerontologists, must be aware of the problems that the treatment of psoriasis in the elderly can present. This is especially important because of the increased risk of adverse drug reactions in the elderly.

Spontaneous release of leukemia inhibitory factor and oncostatin-M is increased in supernatants of short-term organ cultures from lesional psoriatic skin.

Several cytokines are increased in psoriatic skin, mainly at the lesional level. Some of these mediators seem to be very important in the pathogenesis of psoriasis since they are thought to stimulate keratinocyte proliferation and/or to drive the inflammatory changes associated with psoriasis. Among the proinflammatory modulators, hematopoietins, which are a family of cytokines sharing a receptor component (the gp130 subunit), have been under intensive investigation in recent years. The hematopoietin family includes interleukin-6 (IL-6), interleukin-11 (IL-11,) leukemia inhibitory factor (LIF), oncostatin-M (OSM), granulocyte colony-stimulating factor (G-CSF), ciliary neurotrophic factor (CNTF) and cardiotrophin. Amounts of two of these molecules, IL-6 and IL-11, have been found to be increased in psoriatic lesions. The present study adds new information concerning the spontaneous release of two hematopoietins, namely LIF and OSM, in 48-h culture supernatants of lesional and nonlesional skin punch biopsies from psoriatic patients and normal subjects. The cytokine determinations were performed using commercially available ELISA kits. The results are expressed as picograms per milligram of tissue, after weight normalization. The levels of LIF released by lesional skin (median 2.4 pg/mg, range 0.05-13.4 pg/mg) were significantly higher than from nonlesional (median 0.4 pg/mg, range under detection limit (UDL)-4.4 pg/mg; P = 0.001) and normal skin (median 0.4 pg/mg, range UDL-0.9 pg/mg; P = 0.005). The OSM levels were also significantly higher in supernatants of lesional skin (median 0.9 pg/mg, range 0.4-5.2 pg/mg) than in supernatants of nonlesional (median 0.2 pg/mg, range UDL-0.8 pg/mg; P = 0.001) and normal skin (median 0.1 pg/mg, range UDL-0.4 pg/mg; P = 0.0001). In addition, interleukin-8 (IL-8), a cytokine involved in the pathomechanisms of psoriasis, showed a similar behaviour when measured in the same samples. Lesional skin showed a median value of 752.5 pg/mg, range 98.8-2063.8 pg/mg, nonlesional skin a median value of 58.3 pg/mg, range UDL-1252.5 pg/mg (P = 0.007) and normal skin a median value of 44.6 pg/mg, range UDL-176.7 pg/mg (P = 0.004). No significant differences were found between nonlesional and normal skin for the three molecules analyzed. Taken together with the fact that at least two other hematopoietins (namely IL-6 and IL-11) are also increased in supernatants of lesional psoriatic skin, these data point to a possible involvement of the hematopoietins in inflammatory processes associated with psoriasis.