Work in inflammatory and degenerative joint diseases

This article focuses on work disability and sick leave and their cost; it also discusses the value of vocational rehabilitation programmes in rheumatic conditions such as rheumatoid arthritis, ankylosing spondylitis, hip and knee osteoarthritis. It acknowledges the importance of work not only for the worker who has one of these diseases but also for the public purse. Much can be done to improve the health of the persons and reduce their disability and its impact in the workplace which will have an important effect on their and their family's quality of life. It is important that neither rehabilitation nor vocational rehabilitation are regarded as bolt-on activities after drug treatment but are seen as an integral part of effective management. Publications dealing with return to work are relatively common in rheumatoid arthritis, less common in ankylosing spondylitis and relatively rare in osteoarthritis. Vocational rehabilitation programmes should aim to facilitate job retention or, failing that, to improve the ability to return to work. The process must be started with in the health arena and it has to be recognised that slow or poor practice in the health service can jeopardise the patient's work potential

Identification of novel elements of the Drosophila blisterome sheds light on potential pathological mechanisms of several human diseases.

Main developmental programs are highly conserved among species of the animal kingdom. Improper execution of these programs often leads to progression of various diseases and disorders. Here we focused on Drosophila wing tissue morphogenesis, a fairly complex developmental program, one of the steps of which - apposition of the dorsal and ventral wing sheets during metamorphosis - is mediated by integrins. Disruption of this apposition leads to wing blistering which serves as an easily screenable phenotype for components regulating this process. By means of RNAi-silencing technique and the blister phenotype as readout, we identify numerous novel proteins potentially involved in wing sheet adhesion. Remarkably, our results reveal not only participants of the integrin-mediated machinery, but also components of other cellular processes, e.g. cell cycle, RNA splicing, and vesicular trafficking. With the use of bioinformatics tools, these data are assembled into a large blisterome network. Analysis of human orthologues of the Drosophila blisterome components shows that many disease-related genes may contribute to cell adhesion implementation, providing hints on possible mechanisms of these human pathologies.

Effects of rat anti-VEGF antibody in a rat model of corneal graft rejection by topical and subconjunctival routes.

PURPOSE: To compare the effect of a rat anti-VEGF antibody, administered either by topical or subconjunctival (SC) routes, on a rat model of corneal transplant rejection.METHODS: Twenty-four rats underwent corneal transplantation and were randomized into four treatment groups (n=6 in each group). G1 and G2 received six SC injections (0.02 ml 10 µg/ml) of denatured (G1) or active (G2) anti-VEGF from Day 0 to Day 21 every third day. G3 and G4 were instilled three times a day with denatured (G3) or active (G4) anti-VEGF drops (10 µg/ml) from Day 0 to Day 21. Corneal mean clinical scores (MCSs) of edema (E), transparency (T), and neovessels (nv) were recorded at Days 3, 9, 15, and 21. Quantification of neovessels was performed after lectin staining of vessels on flat mounted corneas.RESULTS: Twenty-one days after surgery, MCSs differed significantly between G1 and G2, but not between G3 and G4, and the rejection rate was significantly reduced in rats receiving active antibodies regardless of the route of administration (G2=50%, G4=66.65% versus G1 and G3=100%; p<0.05). The mean surfaces of neovessels were significantly reduced in groups treated with active anti-VEGF (G2, G4). However, anti-VEGF therapy did not completely suppress corneal neovessels.CONCLUSIONS: Specific rat anti-VEGF antibodies significantly reduced neovascularization and subsequent corneal graft rejection. The SC administration of the anti-VEGF antibody was more effective than topical instillation.

Polymorphisms of the " macrophage migration inhibitory factor " gene in infectious diseases

Summary The proinflammatory cytokine macrophage migration inhibitory factor (MIF) has emerged as a central mediator of inflammation and innate immune defense against infections. MIF has been shown to play an important role in the pathogenesis of infectious diseases like sepsis, tuberculosis and autoimmune inflammatory diseases, such as arthritis, inflammatory bowel disease and asthma. Two functional polymorphisms of the MIF gene promoter, a five to eight CATT repeat microsatellite at position -794 and a G/C SNP at position -173, have been associated with increased susceptibility to or severity of autoimmune inflammatory diseases like arthritis, colitis and atopy. The aim of this thesis was to define whether, and if so by which mechanisms, MIF gene polymorphisms influence the susceptibility to or the outcome of one of the most severe and one of the most prevalent infectious diseases: meningococcal sepsis and tuberculosis, respectively. The results of the comparison between 1106 patients suffering from severe meningococcal infections and 434 healthy volunteers showed that carriers of the CATT5-5 genotype were protected from meningococcemia. A transmission disequilibrium test involving 106 families confirmed this association. At baseline and after stimulation with Neisseria meningitidis, the CATT5 MIF promoter drove lower transcriptional activity than the CATT6 or CATT7 alleles in human monocytic cells and whole blood of CATT5-5 healthy individuals tended to produce less MIF than whole blood of CATT6-6 individuals. Beyond, we describe several new MIF gene polymorphisms in Africans. Genotyping the CATT microsatellite and the -173*G/C SNP revealed great genetic diversity in six African ethnic groups. Comparing 471 African tuberculosis cases and 932 matched healthy controls, we observed ethnicity dependent associations of the -173*G/C and the CATT5-8 with susceptibility to or severity of tuberculosis, but confirmation in larger cohorts ìs needed. In conclusion, we report that homozygous carriage of a low expression allele of the MIF gene protects from meningococcal disease. These results support the concept that analyses of MIF genotypes in patients with sepsis may help to classify patients into risk categories and to identify those patients who may benefit from anti-MIF therapeutic strategies.

Les connectivites: progrès thérapeutiques et place de la biothérapie [Connective tissue diseases: news in therapy, role of biologics agents].

Systemic lupus erythematosus and primary Sjögren's syndrom are the two major connective tissue diseases. A better knowledge of their physiopathology allows us today to propose an adapted therapy. Moreover progress concerns the oldest treatment, hydroxychloroquine, and biotherapy. Hydroxychloroquine is still an actual treatment for lupus, its positive effects are better understood today. Nevertheless it does not seem to be efficient to treat primitive Sjögren. Biotherapy targeting B lymphocytes seems efficient in these two connective tissue diseases. Anti TNF therapy is not recommended and seems to induce connective tissue diseases. The real news is the recent approval and reimbursement in Switzerland of the new drug belimumab (Benlysta) in case of moderate lupus.

Médecine génomique et Maladies infectieuses [Genomic medicine and infectious diseases].

Relentless progress in our knowledge of the nature and functional consequences of human genetic variation allows for a better understanding of the protracted battle between pathogens and their human hosts. Multiple polymorphisms have been identified that impact our response to infections or to anti-infective drugs, and some of them are already used in the clinic. However, to make personalized medicine a reality in infectious diseases, a sustained effort is needed not only in research but also in genomic education.

Les maladies infectieuses ont encore un bel avenir [Infectious diseases have again a good future!].

Invasive fungal diseases (IFDs) have become major causes of morbidity and mortality among highly immunocompromised patients. Authoritative consensus criteria to diagnose IFD have been useful in establishing eligibility criteria for antifungal trials. There is an important need for generation of consensus definitions of outcomes of IFD that will form a standard for evaluating treatment success and failure in clinical trials. Therefore, an expert international panel consisting of the Mycoses Study Group and the European Organization for Research and Treatment of Cancer was convened to propose guidelines for assessing treatment responses in clinical trials of IFDs and for defining study outcomes. Major fungal diseases that are discussed include invasive disease due to Candida species, Aspergillus species and other molds, Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides immitis. We also discuss potential pitfalls in assessing outcome, such as conflicting clinical, radiological, and/or mycological data and gaps in knowledge.

The inflammasome, autoinflammatory diseases, and gout.

IL-1beta is a cytokine with major roles in inflammation and innate immune responses. IL-1beta is produced as an inactive proform that must be cleaved within the cell to generate biologically active IL-1beta. The enzyme caspase-1 catalyzes the reaction. Recent work showed that caspase-1 must be activated by a complex known as the inflammasome. The inflammasome comprises NALP, which is an intracellular receptor involved in innate immunity, and an ASC adapter that ensures caspase-1 recruitment to the receptor. The most extensively described inflammasome to date is formed by the NALP3 receptor within monocytes. Mutations involving the NALP3 gene cause hereditary periodic fever syndromes in humans. Increased inflammasome activity responsible for uncontrolled IL-1beta production occurs in these syndromes. Inhibition of the IL-1beta pathway by IL-1 receptor antagonist (anakinra) is a highly effective treatment for inherited periodic fever syndromes. A major role for inflammasome activity in the development of gout attacks was established recently. Urate monosodium crystals are specifically detected via the NALP3 inflammasome, which results in marked IL-1beta overproduction and initiation of an inflammatory response. This finding opens up new possibilities for the management of gouty attacks.

Nouvelles thérapies pour les maladies osseuses de l'enfant [New therapies for children affected by bone diseases].

Considerable progress has been achieved in recent years in treating children affected by bone diseases. Advances in the understanding of the molecular pathophysiology of genetic bone diseases have led to the development of enzyme replacement therapies for various lysosomal storage diseases, following the breakthrough initiated in treating Gaucher disease. Clinical studies are underway with tailored molecules correcting bone fragility and alleviating chronic bone pain and other manifestations of hypophosphatasia, or promoting growth of long bones in achondroplasia patients. We further report our very encouraging experience with intravenous bisphosphonate treatment in children suffering from secondary osteopenia and the high prevalence of calcium and vitamin D deficits in these severely disabled children.

Alterations of bone microarchitecture in young patients with inflammatory bowel diseases are associated with fracture risk during growth

Aims: Inflammatory bowel diseases (IBD) appearing during childhood and adolescence compromise peak bone mass acquisition and increase fracture risk. The structural determinants of bone fragility in IBD however remain unknown. Methods: We investigated volumetric bone mineral density (vBMD), trabecular and cortical bone microstructure at distal radius and tibia by high-resolution pQCT (XtremeCT, Scanco, Switzerland), aBMD at distal radius, hip and spine and vertebral fracture assessment (VFA) by DXA in 107 young patients (mean age 22.8 yrs, range 12.2-33.7 yrs; 62 females and 45 males) with Crohn's disease (n=75), ulcerative colitis (n=25), undetermined colitis (n=2), and no definitive diagnosis (n=5), and in 389 healthy young individuals. Results: Mean disease duration was 6.1 yrs, 89/107 IBD patients received corticosteroids, 83 other immunomodulators, and 59 vitamin D. Clinical fractures were reported by 38 patients (mean age at 1st fracture, 12.6 yrs), the vast majority of the forearm, arm or hand; 5 had vertebral crush fractures (Grade 1 or 2) and 11 had multiple fractures. As compared to healthy controls (matched 2:1 for age, sex, height and fracture history), the 102 patients with established IBD had similar weight but significantly lower aBMD at all sites, lower trabecular (Tb) BV/TV and number, and greater Tb separation and inhomogeneous Tb distribution (1/SD TbN) at both distal radius and tibia, lower tibia cortical thickness (CTh), but no differences in cortical vBMD nor bone perimeter. Among IBD's, aBMD was not associated with fractures (by logistic regression adjusted for age, age square, sex, height, weight and protein intake). However, radius and tibia Tb BV/TV, thickness and SD 1/TbN, as well as radius Tb separation and perimeter, were significantly associated with fracture risk (fully adjusted as above), whereas cortical vBMD and CTh were not. After adjustment for aBMD at radius, respectively at femur neck, radius SD 1/TbN and tibia BV/TV, TbTh and perimeter remained independently associated with fracture risk. Conclusions: Young subjects with IBD have low bone mass and poor bone microarchitecture compared to healthy controls. Alterations of bone microarchitecture, particularly in the trabecular bone compartment, are specifically associated with increased fracture risk during growth.

Der akute anale Schmerz [Acute anal pain].

Acute anal pain is a common proctological problem. A detailed history together with the clinical examination are crucial for the diagnosis. An acute perianal vein thrombosis can be successfully excised within the first 72 hours. Acute anal fissures are best treated conservatively using stool regulation and topical medications reducing the sphincter spasm. A chronic anal fissure needs surgery. Perianal abscesses can very often be incised and drained in local anesthesia. Proctalgia fugax and the levator ani syndrome are exclusion diagnoses and are treated symptomatically.