Novel Therapeutic Approaches in Rheumatoid Arthritis: Role of Janus Kinases Inhibitors.

Rheumatoid Arthritis (RA) is a chronic inflammatory disease characterized by synovial inflammation and hyperplasia, autoantibody production, cartilage and bone destruction and several systemic features. Cardiovascular, pulmonary, psychological, and muscle involvement are the main comorbidities of RA and are responsible for the severity of the disease and long-term prognosis. Pharmacological treatment of rheumatic diseases has evolved remarkably over the past years. In addition, the widespread adoption of treat to target and tight control strategies has led to a substantial improvement of outcomes, so that drug-free remission is nowadays a realistic goal in the treatment of RA. However, despite the availability of multiple therapeutic options, up to 40% of patients do not respond to current treatments, including biologics. Small-molecule therapies offer an alternative to biological therapies for the treatment of inflammatory diseases. In the past 5 years, a number of small-molecule compounds targeting Janus Kinases (JAKs) have been developed. Since JAKs are essential for cell signaling in immune cells, in particular controlling the response to many cytokines, their inhibitors quickly became a promising class of oral therapeutics that proved effective in the treatment of RA. Tofacitinib is the first Janus Kinase (JAK) inhibitor approved for the treatment of RA, followed more recently by baricitinib. Several other JAK inhibitors, are currently being tested in phase II and III trials for the treatment of a different autoimmune diseases. Most of these compounds exhibit an overall acceptable safety profile similar to that of biologic agents, with infections being the most frequent adverse event. Apart from tofacitinib, safety data on other JAK inhibitors are still limited. Long-term follow-up and further research are needed to evaluate the general safety profile and the global risk of malignancy of these small molecules, although no clear association with malignancy has been reported to date. Here, we will review the main characteristics of JAK inhibitors, including details on their molecular targets and on the clinical evidences obtained so far in the treatment of RA

Effects of Polyurethane Foam Dressings as an Add-on Therapy in the Management of Digital Ulcers in Scleroderma Patients.

Digital ulcers (DUs) represent a severe and common complication occurring in patients affected by Systemic Sclerosis (SSc), with a consistent impact on the quality of life and often resulting in longer hospitalization than unaffected patients. Conventional treatment of SSc ulcers consists of both topical and systemic (oral or intravenous) pharmacological therapies. Several surgical options are also available, but there is overall a lack of official guidelines or recommendations. The aim of this study was to evaluate the efficacy of a novel local therapy based on polyurethane foam dressings, namely the Highly Hydrophilic Polyurethane Foam (HPF), in addition to the conventional pharmacological treatment, in a cohort of 41 SSc patients with at least one active ulcer. Our results showed that the addition of HPF to the conventional treatment based on systemic drugs induced i) a significant reduction in the number of active DUs (p=0.0034); ii) a significant reduction of the mean duration of ulcer-related hospitalization as compared with standard therapy (p=0.0001); iii) a significant improvement of patients' Quality of Life, as evaluated through the Scleroderma Health Assessment Questionnaire (SHAQ) (p=0.00011). Therefore, in our experience, the combined management of DUs can improve both the onset of new DUs and DU's healing thus leading to a better outcome

Immunosuppressive therapy with rituximab in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent symptomatic primary antibody deficiency in adulthood and is characterized by the marked reduction of IgG and IgA serum levels. Thanks to the successful use of polyvalent immunoglobulin replacement therapy to treat and prevent recurrent infections, non-infectious complications, including autoimmunity, polyclonal lymphoproliferation and malignancies, have progressively become the major cause of morbidity and mortality in CVID patients. The management of these complications is particularly challenging, often requiring multiple lines of immunosuppressive treatments. Over the last 5-10 years, the anti-CD20 monoclonal antibody (i.e., rituximab) has been increasingly used for the treatment of both autoimmune and non-malignant lymphoproliferative manifestations associated with CVID. This review illustrates the evidence on the use of rituximab in CVID. For this purpose, first we discuss the mechanisms proposed for the rituximab mediated B-cell depletion; then, we analyze the literature data regarding the CVID-related complications for which rituximab has been used, focusing on autoimmune cytopenias, granulomatous lymphocytic interstitial lung disease (GLILD) and non-malignant lymphoproliferative syndromes. The cumulative data suggest that in the vast majority of the studies, rituximab has proven to be an effective and relatively safe therapeutic option. However, there are currently no data on the long-term efficacy and side effects of rituximab and other second-line therapeutic options. Further randomized controlled trials are needed to optimize the management strategies of non-infectious complications of CVID

The Urokinase/Urokinase Receptor System in Mast Cells: Effects of its Functional Interaction with fMLF Receptors.

Mast cell and basophils express the high affinity receptor for IgE (FcɛRI) and are primary effector cells of allergic disorders. The urokinase (uPA)-mediated plasminogen activation system is involved in physiological and pathological events based on cell migration and tissue remodelling, such as inflammation, wound healing, angiogenesis and metastasis. uPA is a serine protease that binds uPAR, a high affinity glycosyl-phosphatidyl-inositol (GPI)-anchored receptor. uPAR focuses uPA activity at the cell surface and activates intracellular signaling through lateral interactions with integrins, receptor tyrosine kinases and the G-protein-coupled family of fMLF chemotaxis receptors (FPRs). We investigated the expression of the uPA-uPAR system and its functional interaction with FPRs in human mast cells (MCs). Differently from basophils, MCs produced uPA that was able to induce their chemotaxis. Indeed, MCs also expressed uPAR, both in the intact and in a cleaved form (DII-DIII-uPAR) that can expose, at the N-terminus, the SRSRY sequence, able to interact with FPRs and to mediate cell chemotaxis. MCs also expressed mRNAs for FPRs that were functionally active; indeed, uPA and a soluble peptide (uPAR84-95), containing the SRSRY chemotactic sequence of uPAR and able to interact with FPRs, were able to induce MCs chemotaxis. Thus, uPA is a potent chemoattractant for MCs acting through the exposure of the chemotactic epitope of uPAR, that is an endogenous ligand for FPRs. The same mechanism could be involved in VEGF-A secretion by human MCs, also induced by uPA and uPAR84-95 stimulation

Reverse left ventricular remodeling is more likely in non ischemic cardiomyopathy patients upgraded to biventricular stimulation after chronic right ventricular pacing

<p>Abstract</p> <p>Background</p> <p>Chronic right ventricular (RV) apical pacing may lead to left ventricular (LV) dyssynchrony and LV dysfunction. In heart failure due to RV pacing, upgrading to biventricular stimulation (CRT) can improve NYHA Class and LV function. A proportion of patients do not respond to upgrading. Aim was to assess whether etiology of LV dysfunction accounts for responses to CRT in RV-paced patients.</p> <p>Methods</p> <p>Sixty-two patients treated by CRT, under RV pacing from 50.2 ± 5.4 months, were studied. Cause of LV dysfunction was non-ischemic (NIC) in 28 and ischemic cardiomyopathy (IC) in 34 patients. Clinical and conventional echocardiographic parameters were available within 1 month before RV pacing, within 1 month before CRT and at 12 ± 2 months of follow-up (FU).</p> <p>Results</p> <p>Decreased LVEF (from 37.0 ± 8.8 to 25.6 ± 6.1%, p <0.001), increased LV end-systolic dimensions (LVESD) (from 48.1 ± 8.6 to 55.2 ± 7.9 mm, p <0.001) and worsened NYHA Class (from 1.9 ± 1.1 to 3.2 ± .6, p < 0.005) were found before CRT, compared to pre RV-pacing. After CRT, 44/62 patients showed a ≥ 1 NYHA Class improvement; >10% decrease in LVESD was observed in 24 patients: 5 with IC, 19 with NIC (p < .0.001). The association between cause of LV dysfunction with >10% decrease in LVESD remained highly significant (p < 0.001) adjusting for pre-CRT QRS duration, NYHA Class, LVEF, LVESD, treatment or RV pacing duration.</p> <p>Conclusions</p> <p>CRT improves functional class even after long-lasting pacing. Reverse remodeling is evident in a small population, more likely with NIC.</p

Caregivers' active role in palliative home care – to encourage or to dissuade? A qualitative descriptive study

<p>Abstract</p> <p>Background</p> <p>Spouses' involvement in palliative care is often a prerequisite for home death, but it is unclear whether active involvement of the spouse, e.g. administering and being in charge of oral or subcutaneous medication or taking care of the patient's personal hygiene, could be harmful or have negative effects on the spouse's experience of the palliative course of disease. The aim of this study was to explore the impact of bereaved spouses' active involvement in medical and physical care on their experience of the palliative course of disease.</p> <p>Methods</p> <p>The study was a qualitative, descriptive study based on semi-structured individual interviews with seven bereaved spouses.</p> <p>Results</p> <p>Four main categories were found: Degree of involvement, Positive and Negative impact and Prerequisites. The prerequisites found for a positive outcome were Safety (24-hour back-up), Confidence (Professionals' confidence in the spouses' abilities) and Dialog (Spouses' influence on decision-making and being asked).</p> <p>Conclusion</p> <p>The results from this study identified important issues whenever spouses take an active part in medical treatment and physical care of critically ill patients in palliative care. The results question the previous research that active involvement of family care givers could be harmful and add preconditions to a positive outcome. More research into these preconditions is needed.</p

Observation of an Exotic S=+1S=+1 Baryon in Exclusive Photoproduction from the Deuteron

In an exclusive measurement of the reaction $\gamma d \to K^+ K^- p n$, a narrow peak that can be attributed to an exotic baryon with strangeness $S=+1$ is seen in the $K^+n$ invariant mass spectrum. The peak is at $1.542\pm 0.005$ GeV/c$^2$ with a measured width of 0.021 GeV/c$^2$ FWHM, which is largely determined by experimental mass resolution. The statistical significance of the peak is $5.2 \pm 0.6 \sigma$. The mass and width of the observed peak are consistent with recent reports of a narrow $S=+1$ baryon by other experimental groups.Comment: 5 pages, 5 figure

Measurement of Beam-Spin Asymmetries for Deep Inelastic π+\pi^+ Electroproduction

We report the first evidence for a non-zero beam-spin azimuthal asymmetry in the electroproduction of positive pions in the deep-inelastic region. Data have been obtained using a polarized electron beam of 4.3 GeV with the CLAS detector at the Thomas Jefferson National Accelerator Facility (JLab). The amplitude of the $\sin\phi$ modulation increases with the momentum of the pion relative to the virtual photon, $z$, with an average amplitude of $0.038 \pm 0.005 \pm 0.003$ for $0.5 < z < 0.8$ range.Comment: 5 pages, RevTEX4, 3 figures, 2 table