[Clinical efficacy of mechanical bacterial lysate in the prevention of infectious exacerbations of chronic obstructive pulmonary disease].

AIM: To evaluate the efficacy of mechanical bacterial lysate on the prevention of infectious exacerbations of chronic obstructive pulmonary disease in patients with frequent exacerbations. MATERIALS AND METHODS: The study included patients (n=60) with frequent exacerbations of COPD (groups C and D according to the GOLD classification). All COPD patients were divided into two groups by blind method. The first group (n=30) received conventional therapy for COPD plus MBL (the course included 3 cycles of 10 days therapy with 20-day intervals between them). The second group of patients (control, n=30) received conventional therapy for COPD without MBL.We evaluated the severity of symptoms, frequency of recurrence of COPD exacerbations, readmissions, need for emergency care and changes in basic therapy of COPD. Evaluations were done on 10 days, 1, 3 and 6 months from the start of the study. RESULTS: Adding of MBL to the therapy list of COPD resulted in a significant decrease of biomarkers of systemic inflammation and sputum purulence during compared to the control group. After 6 months of observation MBL group demonstrated statistically significant improvement of respiratory function, decrease in frequency of COPD exacerbations, needs for emergency medical service, reduced changes in basic therapy and hospitalization for exacerbation of COPD. Therapy with MBL showed a high degree of safety and low incidence of adverse events. CONCLUSION: The results of the study indicate that MBL may be used for the prevention of severe infectious exacerbations of COPD.

2016 updated EULAR evidence-based recommendations for the management of gout.

BACKGROUND: New drugs and new evidence concerning the use of established treatments have become available since the publication of the first European League Against Rheumatism (EULAR) recommendations for the management of gout, in 2006. This situation has prompted a systematic review and update of the 2006 recommendations. METHODS: The EULAR task force consisted of 15 rheumatologists, 1 radiologist, 2 general practitioners, 1 research fellow, 2 patients and 3 experts in epidemiology/methodology from 12 European countries. A systematic review of the literature concerning all aspects of gout treatments was performed. Subsequently, recommendations were formulated by use of a Delphi consensus approach. RESULTS: Three overarching principles and 11 key recommendations were generated. For the treatment of flare, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), oral or intra-articular steroids or a combination are recommended. In patients with frequent flare and contraindications to colchicine, NSAIDs and corticosteroids, an interleukin-1 blocker should be considered. In addition to education and a non-pharmacological management approach, urate-lowering therapy (ULT) should be considered from the first presentation of the disease, and serum uric acid (SUA) levels should be maintained at<6 mg/dL (360 µmol/L) and <5 mg/dL (300 µmol/L) in those with severe gout. Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended. CONCLUSIONS: These recommendations aim to inform physicians and patients about the non-pharmacological and pharmacological treatments for gout and to provide the best strategies to achieve the predefined urate target to cure the disease.

Treat-to-target (T2T) recommendations for gout.

OBJECTIVES: The treat-to-target (T2T) concept has been applied successfully in several inflammatory rheumatic diseases. Gout is a chronic disease with a high burden of pain and inflammation. Because the pathogenesis of gout is strongly related to serum urate levels, gout may be an ideal disease in which to apply a T2T approach. Our aim was to develop international T2T recommendations for patients with gout. METHODS: A committee of experts with experience in gout agreed upon potential targets and outcomes, which was the basis for the systematic literature search. Eleven rheumatologists, one cardiologist, one nephrologist, one general practitioner and one patient met in October 2015 to develop T2T recommendations based on the available scientific evidence. Levels of evidence, strength of recommendations and levels of agreement were derived. RESULTS: Although no randomised trial was identified in which a comparison with standard treatment or an evaluation of a T2T approach had been performed in patients with gout, indirect evidence was provided to focus on targets such as normalisation of serum urate levels. The expert group developed four overarching principles and nine T2T recommendations. They considered dissolution of crystals and prevention of flares to be fundamental; patient education, ensuring adherence to medications and monitoring of serum urate levels were also considered to be of major importance. CONCLUSIONS: This is the first application of the T2T approach developed for gout. Since no publication reports a trial comparing treatment strategies for gout, highly credible overarching principles and level D expert recommendations were created and agreed upon.

Intravesical treatment of advanced urothelial bladder cancers with oncolytic HSV-1 co-regulated by differentially expressed microRNAs.

Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, local administration of oncolytic Herpes Simplex virus (oHSV-1) can provide a promising new therapy for this disease. However, its inherent neurotoxicity has been a perceived limitation for such application. In this study, we present a novel microRNA-regulatory approach to reduce HSV-1-induced neurotoxicity by suppressing viral replication in neurons while maintaining oncolytic selectivity toward urothelial tumors. Specifically, we designed a recombinant virus that utilizes differentially expressed endogenous microR143 (non-cancerous, ubiquitous) and microR124 (neural-specific) to regulate expression of ICP-4, a gene essential for HSV-1 replication. We found that expression of ICP-4 must be controlled by a combination of both miR143 and miR124 to achieve the most effective attenuation in HSV-1-induced toxicity while retaining maximal oncolytic capacity. These results suggest that interaction between miR143 and miR124 may be required to successfully regulate HSV-1 replication. Our resent study is the first proof-in-principle that miRNA combination can be exploited to fine-tune the replication of HSV-1 to treat human cancers.

Balancing risk and benefit of extended pelvic lymph node dissection in patients undergoing radical cystectomy.

PURPOSE: The optimal extent of pelvic lymph node dissection (PLND) during radical cystectomy (RC) in patients with urothelial carcinoma of the bladder (UCB) is the subject of ongoing debate. In this study, we compared local recurrence-free and overall survival, in addition to complication rates, after extended PLND (ePLND) compared to standard PLND (sPLND). METHODS: We reviewed the charts of 314 patients who underwent RC for UCB between 2008 and 2013. ePLND was performed in 105 patients, and 105 matched patients who underwent standard PLND (sPLND) were selected based on clinical parameters. Local recurrence-free and overall survival rates were assessed using Kaplan-Meier survival analysis, and Cox proportional hazards models were used to assess potential determinants of these outcomes. Complications were assessed at 30 and 90 days using the Clavien-Dindo reporting system. RESULTS: More lymph nodes were removed by ePLND (median 21) compared to sPLND (median 9; P < 0.001), but the rate of nodal involvement was not different. In multivariable analysis, ePLND was associated with a better local recurrence-free survival (HR = 0.63, P = 0.005), but was not an independent predictor of overall survival (HR = 1.06, P = 0.84). Estimated blood loss was greater with ePLND (1047.3 vs. 584.5 ml P < 0.001), but there was no significant difference in complications. CONCLUSIONS: Extended PLND appears to reduce the risk of local recurrence, but was not an independent predictor of overall survival in this cohort. ePLND was associated with greater blood loss compared to sPLND, but not with other perioperative complications.

[Giant cell arteritis: guidelines of the University Hospital of Lausanne]. / Artérite de Horton: recommandations Lausannoises de prise en charge.

Giant cell arteritis (GCA) is a subacute/chronic vasculitis and represents the most common form of systemic vasculitis in people over the age of 50 years. The absence of clear and specific diagnostic criteria with the highly variable clinical presentation is a diagnostic challenge requesting a multidisciplinary approach. Yet, GCA is an emergency and the treatment must be initiated very rapidly due to the risk of blindness. This article presents a review of GCA as well as the diagnostic and therapeutic institutional guidelines of the University Hospital of Lausanne.

[Complications and systemic manifestations of rheumatoid arthritis]. / Complications et atteintes systémiques de la polyarthrite rhumatoïde.

Rheumatoid arthritis (RA), in addition to the traditional joint damage can affect all organs as a systemic disease. Extra-articular manifestations of RA are highly variable ranging from rheumatoid nodules (most common) to rheumatoid vasculitis presenting a significant morbidity and mortality (49% at 5 years). With the new algorithms of treatment (earlier) and the use of biologics, the incidence of severe extra-articular manifestations decreases. Regarding the treatment of rheumatoid vasculitis, rituximab looks promising. RA also increases cardiovascular risk and the risk of osteoporosis. It is therefore important to identify these risks and, if appropriate, treat them. Collaboration with the general practitioner is essential in this situation.

Stages of change, barriers, benefits, and preferences for exercise in RA patients: a cross-sectional study.

OBJECTIVES: To determine the distribution of exercise stages of change in a rheumatoid arthritis (RA) cohort, and to examine patients' perceptions of exercise benefits, barriers, and their preferences for exercise. METHODS: One hundred and twenty RA patients who attended the Rheumatology Unit of a University Hospital were asked to participate in the study. Those who agreed were administered a questionnaire to determine their exercise stage of change, their perceived benefits and barriers to exercise, and their preferences for various features of exercise. RESULTS: Eighty-nine (74%) patients were finally included in the analyses. Their mean age was 58.4 years, mean RA duration 10.1 years, and mean disease activity score 2.8. The distribution of exercise stages of change was as follows: precontemplation (n = 30, 34%), contemplation (n = 11, 13%), preparation (n = 5, 6%), action (n = 2, 2%), and maintenance (n = 39, 45%). Compared to patients in the maintenance stage of change, precontemplators exhibited different demographic and functional characteristics and reported less exercise benefits and more barriers to exercise. Most participants preferred exercising alone (40%), at home (29%), at a moderate intensity (64%), with advice provided by a rheumatologist (34%) or a specialist in exercise and RA (34%). Walking was by far the preferred type of exercise, in both the summer (86%) and the winter (51%). CONCLUSIONS: Our cohort of patients with RA was essentially distributed across the precontemplation and maintenance exercise stages of change. These subgroups of patients exhibit psychological and functional differences that make their needs different in terms of exercise counselling.

[Erosive hand osteoarthritis]. / L'arthrose érosive des doigts.

Erosive hand osteoarthritis is common and debilitating. Diagnosis is based on the presence of bone erosions which can appear late. Ultrasonography allows earlier diagnosis. The presence of apatite deposits could be of poor prognosis. Non pharmacological treatment includes the explanation of the inflammatory phenomena involved and the use of splints and physical therapy. Drug therapy includes analgesics, NSAIDs and infiltration of a steroid. Chondroitin sulfates have an analgesic and functional effect proven. DMARDs such as hydroxychloroquine and methotrexate have been used successfully. Some patients also benefited from isotope synoviortheses. New therapeutic ways, based on the pathophysiology of the disease, are new under evaluation.

Towards new business models for R&D for novel antibiotics.

In the face of a growing global burden of resistance to existing antibiotics, a combination of scientific and economic challenges has posed significant barriers to the development of novel antibacterials over the past few decades. Yet the bottlenecks at each stage of the pharmaceutical value chain-from discovery to post-marketing-present opportunities to reengineer an innovation pipeline that has fallen short. The upstream hurdles to lead identification and optimization may be eased with greater multi-sectoral collaboration, a growing array of alternatives to high-throughput screening, and the application of open source approaches. Product development partnerships and South-South innovation platforms have shown promise in bolstering the R&D efforts to tackle neglected diseases. Strategies that delink product sales from the firms' return on investment can help ensure that the twin goals of innovation and access are met. To effect these changes, both public and private sector stakeholders must show greater commitment to an R&D agenda that will address this problem, not only for industrialized countries but also globally.

[The etiology and management of gout]. / Ätiologie und Management der Gicht.

Gout is an inflammatory arthritis caused by monosodium urate (MSU) crystal deposits in and around the joint. The formation of urinary calculi can also occur in gout, but are less common than arthritis. Gout usually presents with recurrent episodes of joint inflammation, which over time lead to tophus formation and joint destruction. In the last decade, significant advances have been made regarding not only the epidemiology and genetics of gout and hyperuricemia but also the mechanisms of inflammation and treatment of gout. In addition, knowledge concerning the key role of interleukin 1 (IL-1) has provided new therapeutic perspectives. However, the current management of gout is often suboptimal, with many Patienten either not receiving adequate treatment or being unable to tolerate existing treatments. New therapeutic agents provide interesting new options for Patienten with difficult-to-treat gouty arthritis.The English full-text version of this is available at SpringerLink (under "Supplemental").

[Canakinumab: a promising treatment in rheumatology]. / Rhumatologie. Canakinumab: un traitement prometteur.

In auto-inflammatory diseases, the role of the inflammasome and the interleukine IL-1beta has recently been shown. Thus, the physiopathology of rare diseases as Cryopyrin-associated periodic syndrome (CAPS) is better understood. In the era of biologics, new treatments targeting IL-1 have been developped. Canakinumab is a fully humanized monoclonal antibody inhibiting specifically IL-1beta Clinical studies have shown its efficacy on clinical symptoms and on inflammatory markers in patients with rare diseases such as CAPS or idiopathic juvenile arthritis, but also in more common rheumatic conditions like gout. Canakinumab has been approved in Switzerland only for the treatment of CAPS. Studies evaluating its effect on cardiovascular diseases are ongoing.

[Rheumatology. TNF alpha-inhibitors: infection risks? Practical recommendations]. / Rhumatologie. Anti-TNF alpha: quels risques infectieux? Recommandations pratiques.

Anti-TNF alpha are immunomodulatory treatments prescribed for some rheumatologic inflammatory diseases (ex: spondylarthropathy, rheumatoid polyarthritis). The randomised studies suggested that anti-TNF alpha therapy is associated with an overall risk of infectious diseases. The results of the observational studies are more reassuring. In this article, we will describe some results of theses studies and propose some practical recommendations in use of the anti-TNF alpha therapy.

Molecular basis of polymorphisms of human complement component C3.

C3 exhibits two common allotypic variants that may be separated by gel electrophoresis and are called C3 fast (C3 F) and C3 slow (C3 S). C3 F, the less common variant, occurs at appreciable frequencies only in Caucasoid populations (gene frequency = 0.20). An increased prevalence of the C3 F allele has been reported in patients with partial lipodystrophy, IgA nephropathy, and Indian childhood hepatic cirrhosis. Studies of the genomic organization of the human C3 gene led to the identification of a single change (C to G) between C3 S and C3 F at nucleotide 364 in exon 3. This leads, at the translation level, to the substitution of an arginine residue (positively charged) in C3 S for a glycine residue (neutral) in C3 F. This substitution results in a polymorphic restriction site for the enzyme HhaI. The resulting restriction fragment length polymorphism (RFLP) was investigated using genomic DNA, amplified using the polymerase chain reaction; there was absolute concordance between the genomic polymorphism and the distribution of C3 S and C3 F in 50 normal subjects. The molecular basis of a second structural polymorphism, defined by the monoclonal antibody HAV 4-1, was also characterized. The polymorphic determinant was identified at codon 314 in the exon 9 of the beta chain where a leucine residue (HAV 4-1+) is substituted for a proline residue (HAV 4-1-). Identification of the amino acid sequences of these polymorphic variants will facilitate characterization of possible functional differences between different allotypes of C3. Three RFLPs (BamHI, EcoRI, and SstI) were located to introns in the C3 gene. There was no allelic association between these three RFLPs, or between the RFLPs and the C3 F/S polymorphic site. Genetic equilibration of these polymorphisms has occurred within a gene of 41 kb.

Clinical and ultrasonographic predictors of joint replacement for knee osteoarthritis: results from a large, 3-year, prospective EULAR study.

OBJECTIVES: To determine clinical and ultrasonographic predictors of joint replacement surgery across Europe in primary osteoarthritis (OA) of the knee. METHODS: This was a 3-year prospective study of a painful OA knee cohort (from a EULAR-sponsored, multicentre study). All subjects had clinical evaluation, radiographs and ultrasonography (US) at study entry. The rate of knee replacement surgery over the 3-year follow-up period was determined using Kaplan-Meier survival data analyses. Predictive factors for joint replacement were identified by univariate log-rank test then multivariate analysis using a Cox proportional-hazards regression model. Potential baseline predictors included demographic, clinical, radiographic and US features. RESULTS: Of the 600 original patients, 531 (88.5%), mean age 67+/-10 years, mean disease duration 6.1+/-6.9 years, had follow-up data and were analysed. During follow-up (median 3 years; range 0-4 years), knee replacement was done or required for 94 patients (estimated event rate of 17.7%). In the multivariate analysis, predictors of joint replacement were as follows: Kellgren and Lawrence radiographic grade (grade > or =III vs or =4 mm vs <4 mm) (HR = 2.63 (95% CI 1.70 to 4.06), p<0.0001); knee pain intensity on a 0-100 mm visual analogue scale (> or =60 vs <60) (HR = 1.81 (95% CI 1.15 to 2.83), p=0.01) and disease duration (> or =5 years vs <5 years) (HR=1.63 (95% CI 1.08 to 2.47), p=0.02). Clinically detected effusion and US synovitis were not associated with joint replacement in the univariate analysis. CONCLUSION: Longitudinal evaluation of this OA cohort demonstrated significant progression to joint replacement. In addition to severity of radiographic damage and pain, US-detected effusion was a predictor of subsequent joint replacement.

EULAR evidence-based recommendations for the diagnosis of knee osteoarthritis.

OBJECTIVE: To develop evidence-based recommendations for the diagnosis of knee osteoarthritis (OA). METHODS: The multidisciplinary guideline development group, representing 12 European countries, generated 10 key propositions regarding diagnosis using a Delphi consensus approach. For each recommendation, research evidence was searched systematically. Whenever possible, the sensitivity, specificity and likelihood ratio were calculated for individual diagnostic indicators and a diagnostic ladder was developed using Bayes' method. Secondary analyses were undertaken to test directly the recommendations using multiple predictive models in two populations from the UK and the Netherlands. Strength of recommendation was assessed by the EULAR visual analogue scale. RESULTS: Recommendations covered the definition of knee OA and its risk factors, subsets, typical symptoms and signs, the use of imaging and laboratory tests and differential diagnosis. Three symptoms (persistent knee pain, limited morning stiffness and reduced function) and three signs (crepitus, restricted movement and bony enlargement) appeared to be the most useful. Assuming a 12.5% background prevalence of knee OA in adults aged > or =45 years, the estimated probability of having radiographic knee OA increased with increasing number of positive features, to 99% when all six symptoms and signs were present. The performance of the recommendations in the study populations varied according to the definition of knee OA, background risk and number of tests applied. CONCLUSION: 10 key recommendations for diagnosis of knee OA were developed using both research evidence and expert consensus. Although there is no agreed reference standard, thorough clinical assessment alone can provide a confident rule-in diagnosis.

Insulin secretion and sensitivity before and after surgical treatment for aldosterone-producing adenoma.

AIM: Primary aldosteronism, which is usually caused by an aldosterone-producing tumour, affects glucose metabolism. The effects of this condition on insulin secretion and insulin sensitivity have remained unclear, however. To gain insight into the influence of primary aldosteronism on glucose tolerance, various parameters related to insulin secretion or insulin sensitivity in patients with an aldosterone-producing tumour were comprehensively analyzed. METHODS: To assess 14 patients with an aldosterone-producing tumour, hyperglycaemic and hyperinsulinaemic-euglycaemic clamp tests as well as oral glucose tolerance tests (OGTTs) were performed before and after tumour excision. Time between presurgical analysis and surgery was 27-559 (194±132) days, and 14-142 (51±38) days between surgery and postsurgical analysis. Various parameters related to insulin secretion or sensitivity as determined by OGTT as well as hyperglycaemic and hyperinsulinaemic-euglycaemic clamp analyses were evaluated. RESULTS: Surgical treatment of tumours ameliorated hypokalaemia and reduced plasma aldosterone levels. First and second phases of insulin secretion during the hyperglycaemic clamp, as well as the insulinogenic index and total insulin secretion measured during OGTT, were also improved after surgery. In addition, the insulin sensitivity index determined during the hyperinsulinaemic-euglycaemic clamp was reduced after surgery. CONCLUSION: Primary aldosteronism impairs insulin secretion.