Lucia Novelli

CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population

INTRODUCTION It is known that warfarin treatment is problematic, due to its narrow therapeutic range and to the great interindividual variability. Numerous papers have shown the important contribution of CYP2C9 and VKORC1 genetic variants to this variability. Recently, a new SNP within the CYP4F2 gene was found associated with warfarin dose in the USA. AIMS The aim of our work was to replicate this study in the Italian population and to assess the new CYP4F2 variant relative contribution in explaining warfarin dose variability with respect to CYP2C9 and VKORC1 genetic variants together with age and weight. MATERIALS & METHODS CYP4F2 rs2108622 genotyping was performed by allelic discrimination assay by TaqMan technology. Analysis of variance and multiple linear regression analyses were carried out to examine the contribution of genetic and nongenetic factors. RESULTS Our TT patients require 5.49 mg/day versus 2.93 mg/day of our CC patients. Analysis of variance indicates that about 7% of mean weekly warfarin dose variance is explained by CYP4F2 genotype. Our linear regression model including CYP4F2, CYP2C9 and VKORC1 genetic variants, age and weight, explains 60.5% of the interindividual variability. CONCLUSION Our data confirm and strengthen the role of this variant.

Asthma and comorbid medical illness

Asthma is associated with several comorbidities but the magnitude of the association has not been clearly defined. We aimed to examine the relationship between asthma and comorbidities using information obtained from the Health Search Database (HSD) owned by the Italian College of General Practitioners (Società Italiana Medici Generici, Florence, Italy). We conducted a population-based retrospective study using information obtained from the HSD. The software system used codes of all the diagnostic records using the 9th revision of the International Classification of Diseases. Asthma appeared to be weakly associated with cardiovascular and hypertensive diseases. Intriguingly, the odds ratio of acute or old myocardial infarction was 0.84 (95% CI 0.77–0.91). Asthma was also weakly associated with depression, diabetes mellitus, dyslipidaemia, osteoporosis and rhinosinusitis. In contrast, it was strongly associated with gastro-oesophageal reflux disease (GORD) and, particularly, allergic rhinitis. Age did not influence the association of asthma with comorbidities whereas sex had a different impact according to the specific comorbidity. Our results indicate that asthma is weakly associated with several comorbidities, whereas its association with allergic rhinitis or GORD is stronger.

High Glucose Enhances Responsiveness of Human Airways Smooth Muscle via the Rho/ROCK Pathway

Glucose moves into airway secretions after a glucose load. Therefore people with diabetes or hyperglycemia spend a significant proportion of each day with glucose in their airways secretions. This study investigated the effects of glucose on isolated human airways and on cultured airway smooth muscle (ASM) cells. Human isolated bronchi were stimulated with acetylcholine, histamine, and transmural stimulation and treated with the selective ROCK inhibitors Y27632 and SB772077B under high-glucose conditions. The effect of high glucose concentrations on intracellular calcium flux and the phosphorylation of MYPT1 in ASM cells was also investigated. High (44 mM for 6 h) glucose, but not mannitol, concentrations led to an enhanced responsiveness of ASM to contractile agents. Y27632 and SB772077B completely abolished (P < 0.05) the enhanced contractile effects with a high-concentration glucose solution, compared with control tissues. In cultured ASM cells, incubation with high glucose concentrations significantly (P < 0.05) enhanced bradykinin-induced intracellular calcium flux and the levels of pMYPT1, which were inhibited by Y27632 (P < 0.05). Our study has demonstrated that high glucose concentrations leads to hyperresponsiveness of human isolated bronchi and enhances intracellular calcium release in cultured ASM cells via a Rho/ROCK- and pMYPT1-dependent pathway, suggesting that this crucial pathway may contribute to the reduced lung function observed in patients with diabetes. These data propose novel targets for the treatment of patients with respiratory diseases that also suffer from diabetes mellitus.

The new era for the treatment of psoriasis and psoriatic arthritis: perspectives and validated strategies.

Psoriatic Arthritis (PsA) is a chronic inflammatory arthropathy associated with psoriasis. Psoriasis (PsO) is a chronic, inflammatory skin disease, characterized by hyperproliferation and aberrant differentiation of keratinocytes. PsA and PsO can be considered as a unique disease and are immune-mediated diseases and both innate and adaptive immunity play a role in their pathogenesis. Initially, PsO and PsA were thought to be Th1-mediated diseases, however, in the last years, several studies have shown the role of interleukin 17 (IL-17) and Th17 cells in the pathogenesis of PsA and PsO. Th17 cells have been detected in dermal infiltrates of psoriatic lesions as well as in synovial fluid. Interleukin (IL)-23, produced by antigen presenting cells (APC), especially by dendritic cells (DC), is the key regulator cytokine for Th17 and IL-17 production. In this review we discuss the role of IL-17 and IL-23 in the pathogenesis of PsO and PsA and their role as therapeutic targets for PsO and PsA treatment.

The prevalence of asthma and COPD in Italy: A practice-based study

We conducted a population-based cross-sectional epidemiologic survey of asthma and COPD in an adult representative national sample using information obtained from the Health Search Database owned by the Italian College of General Practitioners. General Practitioners who had a list of patient population of 909,638 individuals (429,962 men and 479,676 women; man/woman ratio [M/WR]: 0.89) ≥ 14 years old at the end of December 2009 were selected to be representatives of the whole Italian population. Cases of asthma and COPD were identified on the basis of the ICD-9 codes. The total sample included 55,500 (6.10% of the entire population; 5.49% of men and 6.64% of women; M/WR: 0.74) subjects suffering from asthma and 25,762 (2.83% of the entire population; 3.51% of men and 2.23% of women; M/WR: 1.41) subjects suffering from COPD. The asthma/COPD ratio in general population was 2.16. The odds ratio (OR) was chosen because asthma and COPD had a prevalence less than 10%. The OR of developing asthma decreased with age both in men and women, but in the first group of age (15-34 years) it was higher in men vs. women (1.69 vs. 1.00) although it became lower than 1 from 35 years old and up in men and from 75 years old and up in women. On the contrary, the OR of developing COPD became higher than 1 from 55 years old and up both in men and in women and progressively increased with age (in the group 75-84 years, it was 6.16 in men and 4.07 in women, respectively).

Autoantibodies in inflammatory arthritis.

Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides.

Complement system and rheumatoid arthritis: relationships with autoantibodies, serological, clinical features, and anti-TNF treatment

Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies, ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9±26.5 vs 110±25mg/dl, P=0.0012; C4 29.7±10.2 vs 22.7±8.3mg/dl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA- (n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (χ2=22.793, P<0.001). RF levels seem to correlate with complement CH50. The presence of high levels of C3 in RA patients may reflect a pro-inflammatory status and represent a negative prognostic factor for anti-TNF therapy.

Inhaled corticosteroids for chronic obstructive pulmonary disease

Introduction: Current guidelines recommend the use of inhaled long-acting bronchodilators, inhaled corticosteroids (ICSs) and their combinations for maintenance treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD); however, it is questionable whether all COPD patients should be treated, as the long-term use of ICSs is accompanied by side effects. Areas covered: This article reviews the evidence about the effects of ICSs in the treatment of COPD. It mainly focuses on meta-analyses of published data and pooled analyses of primary data. It also offers an overview of pipeline developments. Expert opinion: There is now more evidence that there are subsets of patients (mainly, frequent exacerbators with predominant chronic bronchitis and those with overlap between COPD and asthma) with a favorable response to treatment with ICSs (i.e., reduced progression of lung function loss, reduced exacerbation rate and improved health-related quality of life). Therefore, nowadays, the right question is not whether ICSs should not be used at all unless patients have concomitant asthma, but, instead, which COPD patient can benefit from a therapy with ICSs. Unfortunately, however, the number of studies that have investigated the clinical features that might predict corticosteroid response in COPD is still inadequate.

Long-term ustekinumab therapy of psoriasis in patients with coexisting rheumatoid arthritis and Sjögren syndrome. Report of two cases and review of literature

BACKGROUND Inteleukin (IL)12 and IL23 are two main cytokines involved in the pathogenesis of immune-mediated disease. IL12 is produced by macrophages and B lymphocytes and mediates differentiation of Th1 lymphocytes, while IL23 is a pro-inflammatory cytokine essential for the differentiation of Th17 cells. Ustekinumab is a human monoclonal antibody directed against the p40 protein subunit shared by IL12 and IL23, therefore it blocks the signal transmission of both cytokines. MAIN OBSERVATIONS We present two cases and discuss the long-term efficacy of ustekinumab as a treatment of psoriasis in patients affected by autoimmune diseases, rheumatoid arthritis and Sjögrens syndrome, who presented with severe psoriasis after anti-TNF treatment. CONCLUSIONS To the best of our knowledge, these are the first cases reported in the literature describing the long-term good efficacy of ustekinumab not only on paradoxical forms of psoriasis induced by anti-TNF-α drugs, but also on the articular involvement in a patient affected by RA and in a patient affected by Sjögren syndrome.

A 2-year observational study on treatment targets in psoriatic arthritis patients treated with TNF inhibitors

The aim of this study was to evaluate clinical remission and MDA in PsA patients who started TNF-inhibitors (TNFi) treatment with a 2-year follow-up. Concomitant therapies as well as comorbidities were assessed. Level of concordance of clinimetric indices and the potential predictive factors of remission/MDA were also evaluated. Clinical and laboratory evaluations were prospectively performed in PsA patients at baseline (T0) and after 22 (T22), 54 (T54), and 102 (T102) weeks of treatment. Disease activity and disability were assessed using DAS28, CPDAI, DAPSA, MDA, and HAQ-SpA. The Pearson correlation coefficient, univariate, and multivariate binary logistic regression were performed. A total of 221 PsA patients were included. Cardiovascular diseases and metabolic syndrome (MetS) resulted as the most frequent comorbidities. Clinical remission was achieved by over a half of the patients during the follow-up. Use of concomitant therapies, such as csDMARDs and steroids, was significantly reduced during the follow-up. Agreement among indices of treatment targets by k-statistics was excellent for CPDAI and DAPSA and good for MDA and DAS28 or DAPSA. Female sex and MetS resulted as negative prognostic factors of clinical remission and MDA at all the time points. TNFi are highly effective in achieving treatment targets in PsA patients. DAS28, CPDAI, DAPSA, and MDA show a good agreement. Female sex and MetS are associated with a lower probability to achieve remission in PsA patients.