[About a pediatric patients cohort followed in the adult rheumatology department of CHU Liège]. / À propos d'une cohorte de jeunes patients suivis dans le service de rhumatologie adulte du CHU de Liège.

We realized an observational retrospective study about pediatric patients (between 1 to 18 years) followed at the CHU Liège in an adult rheumatologic service during the last 14 years. This study identified 102 patients who developed the first symptoms during infancy, identifying 39 different diseases. Mainly, we identify cases of idiopathic juvenile arthritis, rheumatoid arthritis, spondylarthropathies, systemic lupus erythematosus, systemic vasculitis, connective tissue diseases, bone diseases, and phosphocalcic metabolic disorders. These observations highlight the difficulties to classify inflammatory articular diseases in young patients. Furthermore, this article may be helpful to identify some specificities in the pediatric population who suffers from rheumatologic diseases and some essential factors to make an optimal transition to adult medicine.

Nous avons réalisé une étude rétrospective observationnelle sur les patients d'âge pédiatrique (1-18 ans) ayant été vus en rhumatologie adulte au CHU de Liège ces 14 dernières années. Cette étude a permis d'identifier 102 patients présentant une pathologie rhumatologique à début pédiatrique pour lesquels 39 diagnostics différents ont été retenus. On retrouve principalement des arthrites juvéniles idiopathiques, mais également des polyarthrites rhumatoïdes, des spondylarthropathies, des lupus érythémateux systémiques, des vascularites systémiques, des pathologies du tissu conjonctif, des pathologies osseuses, ainsi que des troubles du métabolisme phosphocalcique. Ces observations mettent en lumière les difficultés de classification de certaines pathologies articulaires inflammatoires du jeune adulte. Elles permettent également d'identifier les spécificités pédiatriques de ces pathologies rhumatologiques et les éléments essentiels à la réalisation d'une transition optimale vers la médecine adulte.

[Remarkable medical advances in rheumatology : may be ]. / Une révolution thérapeutique en rhumatologie : oui, mais .

The development of new drugs is a significant activity in a university hospital that favors access to therapeutic novelties to patients. Rheumatology, whose drug armamentarium was poor in the 1980s, has benefited from the huge progresses of immunology in the 1980-1990s, allowing a therapeutic revolution in whom the academic hospital of Liège (CHU Liège) has been strongly implicated. First protocols with anti-TNF-? monoclonal antibodies have been applied in 1997. Sixty-one protocols have been initiated in rheumatoid arthritis, 12 in ankylosing spondylitis, 10 in psoriatic arthritis, 9 in systemic erythematosus lupus, 3 in giant cell arteritis, 1 in polymyalgia rheumatica, 5 in osteoarthritis and 4 in osteoporosis. Potential and pitfalls will be discussed disease by disease and also by drug categories. The balance remains globally positive, but remission is far from be reached.

La recherche clinique médicamenteuse est une activité importante dans un hôpital universitaire. Elle valide des nouveautés thérapeutiques et fait bénéficier les patients de traitements novateurs bien avant leur mise sur le marché. La rhumatologie est une discipline dont l'arsenal thérapeutique était pauvre dans les années 1980, et les immenses progrès de l'immunologie, réalisés entre 1980 et 1995, lui ont permis de vivre une véritable révolution thérapeutique à laquelle notre service a amplement participé. C'est en 1997 que les premiers traitements par anticorps monoclonaux anti-TNF-? (les traitements dits biologiques) ont été utilisés au CHU de Liège. Soixante et une études seront initiées dans la polyarthrite rhumatoïde, 12 dans la spondylarthrite ankylosante, 10 dans la polyarthrite psoriasique, 9 dans le lupus érythémateux disséminé, 3 dans l'artérite temporale de Horton, une dans la pseudopolyarthrite rhizomélique, une dans la sclérodermie, 5 dans l'arthrose, 4 dans l'ostéoporose. Les espoirs et les déceptions observées dans les différentes indications, et avec les différentes molécules, sont analysées. Le bilan est globalement positif, mais les résultats encore insuffisants que pour arriver au concept de rémission.

Restriction of spontaneous and prednisolone-induced leptin production to dedifferentiated state in human hip OA chondrocytes: role of Smad1 and ß-catenin activation.

OBJECTIVE: The aetiology of OA is not fully understood although several adipokines such as leptin are known mediators of disease progression. Since leptin levels were increased in synovial fluid compared to serum in OA patients, it was suggested that joint cells themselves could produce leptin. However, exact mechanisms underlying leptin production by chondrocytes are poorly understood. Nevertheless, prednisolone, although displaying powerful anti-inflammatory properties has been recently reported to be potent stimulator of leptin and its receptor in OA synovial fibroblasts. Therefore, we investigated, in vitro, spontaneous and prednisolone-induced leptin production in OA chondrocytes, focusing on transforming growth factor-ß (TGFß) and Wnt/ß-catenin pathways. DESIGN: We used an in vitro dedifferentiation model, comparing human freshly isolated hip OA chondrocytes cultivated in monolayer during 1 day (type II, COL2A1 +; type X, COL10A1 + and type I collagen, COL1A1 -) or 14 days (COL2A1 -; COL10A1 - and COL1A1+). RESULTS: Leptin expression was not detected in day1 OA chondrocytes whereas day14 OA chondrocytes produced leptin, significantly increased with prednisolone. Activin receptor-like kinase 1 (ALK1)/ALK5 ratio was shifted during dedifferentiation, from high ALK5 and phospho (p)-Smad2 expression at day1 to high ALK1, endoglin and p-Smad1/5 expression at day14. Moreover, inactive glycogen synthase kinase 3 (GSK3) and active ß-catenin were only found in dedifferentiated OA chondrocytes. Smad1 and ß-catenin but not endoglin stable lentiviral silencing led to a significant decrease in leptin production by dedifferentiated OA chondrocytes. CONCLUSIONS: Only dedifferentiated OA chondrocytes produced leptin. Prednisolone markedly enhanced leptin production, which involved Smad1 and ß-catenin activation.

[The management of systemic lupus erythematosus with biological therapies]. / Traitement du lupus érythémateux dissémine par les médicaments biologiques.

The efficacy and safety of targeted biological therapies have been analyzed in patients suffering from systemic lupus erythematosus. In renal lupus, infliximab has shown prolonged improvement of the renal function after the induction period (small open studies), whereas abatacept had no significant efficacy (randomised controlled study). In renal and non renal lupus, rituximab did not confirm its efficacy in two randomised controlled studies. In non renal lupus, epratuzumab has shown efficacy in a phase IIb. Belimumab at the high posology of 10 mg/kg has also shown significant efficacy in two large randomised controlled studies.

[Genetic and environmental interactions on the development of rheumatoid arthritis]. / Interactions de la génétique et de l'environnement sur le développement de la polyarthrite rhumatoïde.

Rheumatoid arthritis (RA) more and more becomes a syndrome, rather than a disease, with genetic, hormonal and environmental influences, among which smoking and the microbiota generate focused interest. The shared epitope and PTPN22 loci are associated with RA, and, particularly, with the "classical" form with anti-citrullinated peptide antibodies (ACPA) and IgM-rheumatoid factor (IgM-RF) positivity. Pregnancy is associated with a--temporary--remission of RA. Epidemiological studies have shown that oral contraception, parity and hormonal replacement therapy influence the severity of RA, and, this is still discussed, its incidence. Smoking is the first environmental factor strongly associated with RA, specifically with the shared epitope and with ACPA. The study of the microbiota is a novel emerging field that will help us to better understand patterns and evolution of RA.

[Targeted therapy in inflammatory disease: cytokines]. / Thérapies ciblées en rhumatologie: les cytokines.

Summarizing 15 years of therapeutic development of a discipline into a few lines is not an easy thing to do. There are many potential targets involved in the inflammatory of auto-immune diseases. Due to the development of biotherapies the choice has become larger, and it is now possible to target practically any molecule (cytokine, chemokine or surface receptor for example). Cytokines represent the first example of therapeutic target that played a major role in the revolution of our discipline. The first part of presentation will focus on the pro-inflammatory cytokines (TNFalpha, and interleukines 1 and 6). We shall then, detail the development of a new cytokinic target: BLyS (B lymphocyte stimulator) whose role in the autoimmune diseases appeared recently.

[Rhupus: when rheumatoid arthritis meets lupus]. / Le rhupus: à la frontière entre polyarthrite rhumatoïde et lupus érythémateux disséminé.

There exists diseases in rheumatology fulfilling classification criteria for either rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). They are called "rhupus". We retrospectively analyzed the data base "GLIMS" of the CHU de Liège from the starting date of november 2005 until april 2011 to identified those patients that were positive for the anti-sDNA antibody marker of SLE and for the anti-CCP antibody, marker of RA. Fourteen patients were identified and two other patients were added, one suffering from SLE, and the other from RA, and likely to be rhupus. Of the 16 patients analyzed, 9 were real RA with anti-dsDNA antibodies induced by anti-TNF-alpha therapies. Seven were candidates to be rhupus and 6 were retained. They were all women, with a median age of 51 years and in addition were all anti-SS-A antibody positive.

[Biological therapies in rheumatology]. / Les traitements biologiques en rhumatologie.

Biological therapies consisting of monoclonal antibodies and soluble receptors have revolutionized the care of rheumatologic patients. These therapies ensued from a better understanding of the physiopathology of rheumatologic disorders. Most of the latter have been concerned: rheumatoid arthritis (for about 10 years), psoriatic arthritis and ankylosing spondilitys (for more or less five years). Rheumatology was among the first disciplines to make use of these advances; it continues to benefit from the results of intense research efforts. These developments request from clinicians an increased expertise in immunology.

[Proteomics studies on arthritis by SELDI-TOF-MS: identification of the S100 proteins family as proteins of interest]. / Protéomique par SELDI-TOF-MS des maladies inflammatoires articulaires: identification des protéines S100 comme protéines d'intérêt.

Clinical proteomics is a technical approach studying the entire proteome expressed by cells, tissues or organs. It describes the dynamics of cell regulation by detecting molecular events related to diseases development. Proteomic techniques focus mainly on identification of new biomarkers or new therapeutic targets. It is a multidisciplinary approach using medical, biological, bioanalytical and bioinformatics knowledges. A strong collaboration between these fields allowed SELDI-TOF-MS proteomics studies to be performed at the CHU and the University of Liège, in GIGA-Research facilities. The aim of these studies was driven along three main axes of research related to the identification of biomarkers specific to a studied pathology, to a common biological pathway and, finally, to a treatment response. This work was presented in the setting of the "Synthèse CHU 2009" meeting.

[Biological therapy of inflammatory diseases]. / Le traitement biologique des maladies inflammatoires à médiation immune. Le cas de la dermatologie et de la rhumatologie.

The pathophysiology and the treatment of diseases with clinical presentation so different as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and psoriasis vulgaris have been revolutionized by the discovery of common pro-inflammatory effector mechanisms involving TNF-alpha and by the use of targeted therapies, the anti-TNF-alpha antibodies. In the past 10 years, our experience has helped several hundreds of patients who were treated with novel drugs, years before they became routinely available. In parallel tools of metrology were developped that can now be applied to the routine patient. Lastly, clinical research on these new drugs has also generated derived research works allowing the university hospital to satisfactorilly fullfil its specific missions.

The ability of normal human monocytes to phagocytose IgG-coated red blood cells is related to the number of accessible galactosyl and mannosyl residues in the Fc domain of the anti-red blood cell IgG antibody molecules.

The percentage of normal human monocytes (MCs) that are able to form rosettes with, and subsequently phagocytose, IgG-coated red blood cells (RBCs) has been determined in vitro using five batches of anti-RBC IgG antibodies. These antibodies differed from each other by their capacity to bind to lectins recognizing two of the oligosaccharide structures of the Fc domain, namely, peanut agglutinin (PNA) and concanavalin A (ConA) which specifically bind to beta-galactosyl and alpha-mannosyl residues, respectively. The threshold between high (H) and low (L) binding capacities (BC) was arbitrarily fixed at 15% of mean specific binding. For each level of RBC sensitization tested (1500-6000 Ab molecules/one RBC), the percentage of MCs binding at least three IgG-RBCs was similar whatever the IgG Ab preparations used. In contrast, the percentage of MCs capable of phagocytosing at least three IgG-RBCs coated with 3000, 4500 and 6000 IgG/cell, as well as the phagocytosis index (number of IgG-RBCs ingested/100 MCs) of IgG-RBCs coated with 1500, 3000, 4500 and 6000 IgG/cell, were significantly lower (P less than 0.01 at least) using IgG Ab molecules with either [(PNA-H)(ConA-H)] BC, [(PNA-L) (ConA-H)] BC or with [(PNA-L)(ConA-L)] BC than the corresponding values measured using RBCs coated with IgG Ab molecules exhibiting [(PNA-H)(ConA-L)] BC. The binding to MCs of 125I-labelled anti-RBC IgG Ab molecules exhibiting different binding profiles to PNA and to ConA was studied by Scatchard plot analysis. A single class of binding sites was observed in each case. MCs bound a mean of 23,000 IgG molecules with a mean association constant (Ka) for IgG binding of about 1.4 X 10(8) M-1. These data indicate that terminal (and/or accessible) galactosyl and mannosyl residues of IgG Ab molecules play a role in the ingestion of IgG-RBCs by human MCs, despite the fact IgG Ab binding to IgG(Fc) receptors is not significantly affected. Thus, when studying the phagocytosis of IgG-coated RBC by human MC monolayers, the assay should be performed not only using similar RBC/MC ratios and IgG coating values, but also with IgG antibodies having comparable mean PNA and ConA binding capacities.

In vitro effects of thymopentin on the gamma-interferon production by peripheral blood mononuclear cells from normal subjects and from patients with rheumatoid arthritis.

The in vitro production of gamma-interferon (gamma-IFN) by peripheral blood mononuclear cells (MNC) was measured using a specific radioimmunoassay in 16 patients presenting with active rheumatoid arthritis (RA), in 14 patients with inactive disease, and in 36 control subjects (CS). Unstimulated cultures produced undetectable levels of gamma-IFN and did not incorporate tritiated thymidine. In response to phytohemagglutinin (PHA) 0.2 microgram/ml, MNC from active RA produced 9 times less, and under PHA 2.5 micrograms/ml, 4 times less gamma-IFN than did MNC from inactive RA or from CS. The uptake of tritiated thymidine was, however, similar in the 3 groups. In unstimulated cultures of the 3 groups, thymopentin (TP-5), at all concentrations tested, did not influence either the levels of gamma-IFN or the uptake of tritiated thymidine. In the presence of PHA 0.2 microgram/ml and TP-5, lambda-IFN levels were increased in CS, unchanged in inactive RA and reduced in active RA, whereas no changes were observed in the uptake of tritiated thymidine. Our results show that under our experimental conditions, TP-5 was able to increase the levels of gamma-IFN produced by normal MNC in vitro, but could not reverse the profound defect observed in active RA.

Sarcoidosis: recognition and treatment guidelines.

Sarcoidosis is a systemic disorder of unknown aetiology characterised by noncaseating granulomas leading principally to bilateral hilar lymphadenopathies, pulmonary infiltration and skin and eye lesions. Sarcoidosis may involve other organs, including peripheral lymph nodes, liver, spleen, nervous and musculoskeletal systems, heart, ear, nose and kidney. Although the clinical involvement of liver and heart is relatively uncommon, hepatic and cardiac granulomas are present at autopsy in about 70 to 80% and 25 to 50%, respectively, of patients with this disease. The diagnosis of sarcoidosis includes compatible clinical and/or radiological presentations and histological evidence of noninfectious and noncaseating epitheloid cell granulomas in the absence of other identifiable agents responsible for such histological lesions. Disease course is variable and usually characterised by frequent remissions, but it may become progressive and chronic in a small percentage of patients. The optimal treatment of sarcoidosis remains poorly defined. In patients with progressive pulmonary dysfunction as well as in those with severe extrapulmonary localisations, systemic corticosteroids usually represent the first approach, limited by long term toxicity and frequent relapses after treatment interruption. In the presence of refractory or corticosteroid-dependent forms of the disease, antimalarial drugs or low dosage methotrexate may be used with prolonged benefit. The indications for immunosuppressive agents such as azathioprine, chlorambucil, cyclophosphamide and cyclosporin are uncommon and limited because of potentially serious adverse effects and lack of information on their long term efficacy. In the case of ocular and limited cutaneous manifestations, local corticosteroid therapy may be useful.

Increased synovial fluid levels of interleukin-12, sCD25 and sTNF-RII/sTNF-RI ratio delineate a cytokine pattern characteristic of immune arthropathies.

The assessment of cytokines and their soluble receptors in the synovial fluid (SF) of inflammatory arthropathies may be useful in studying pathogenetic and immunoregulatory mechanisms underlying different diseases. The aim of this work was to study the cytokine network occurring in inflammatory arthropathies and to identify a cytokine profile which is characteristic of an immune-mediated synovitis. Levels of IL-12, as well as IL-4, IL-8, IL-10, IFN-gamma, sCD25, TNF-alpha and its soluble receptors were measured in the SF of various arthropathies, i.e. non-inflammatory arthropathies: "control" meniscus pathology (n = 21), osteoarthritis (n = 22) and chronic crystal arthritis (n = 9); a non-immune inflammatory arthropathy: acute crystal arthritis (n = 11); 2 immune inflammatory arthropathies: reactive arthritis (ReA) (n = 23) and rheumatoid arthritis (RA) (n = 44). SF levels of IL-10, TNF-alpha and sTNF-RII were found to be increased in the three inflammatory arthropathies compared to the "control" meniscus group. Within the inflammatory group, acute crystal arthritis was characterized by a significantly higher sTNF-RI/TNF-alpha ratio and ReA by a significantly lower sTNF-RII/TNF-alpha ratio compared to the two other diseases. The two immune arthropathies, RA and ReA, were characterized by increased SF levels of IL-12, sCD25 and of the sTNF-RII/sTNF-RI ratio. ReA differed however from RA by showing lower IL-8 and IL-4 levels, higher IFN-gamma levels and a higher IL-12/IL-10 ratio, suggesting a more prevalent Th1 profile in ReA SF. Our data indicate that the measurement of SF cytokines and soluble receptors may discriminate between each inflammatory arthropathy and might be useful in clinical practice.

The use of Sandimmun (cyclosporin A) in severe refractory rheumatoid arthritis: the Belgian experience.

OBJECTIVE: To investigate practicability, efficacy and tolerability of low starting doses of Sandimmun (cyclosporin A) (2.5 mg/kg daily) in patients with severe refractory rheumatoid arthritis in the short (6 months) and middle (12 months) term. METHODS: Fifty-nine patients, presenting with active and severe rheumatoid arthritis unresponding to conventional DMRADs were allowed to start Sandimmun at the dose of 2.5 mg/kg daily. This dose was progressively increased by steps of 25 mg daily up to a maximum of 5 mg/kg daily according to the renal function and blood pressure. RESULTS: A mean maintenance dose of 3.9 mg/kg daily was reached after 5 months and maintained throughout the study. Twenty-one patients (36%) completed the one year study. The reasons for discontinuation were: inefficacy (13), adverse events (17), both inefficacy and adverse events (5) and non-compliance (3). For those patients who completed the trial, clinical relevant improvements were observed within 3 months of treatment and were maintained until the end of the study for the Lee functional and the Ritchie articular index, as well as for the number of tender and swollen joints. No changes for the grip strength, the biological and immunological parameters were observed. Mean serum creatinine values rose from 0.81 mg/dl at start to 1.1 mg/dl after 5 months of therapy and remained at that level throughout the study. In patients who discontinued, the serum creatinine level nearly normalized after one month of Sandimmun withdrawal. One hundred and sixty-two side effects were reported of which most were minor and known to occur with Sandimmun. Twenty-two cases (37% of patients) dropped out for adverse events before 1 year treatment. The criteria to withdraw the patients from the study differed greatly from centre to centre. CONCLUSIONS: Managing RA patients presenting with very long and severe disease remains difficult. Therefore low dose Sandimmun (2.5-5 mg/kg daily) appears to be a valuable therapeutic opportunity in RA patients refractory to various other conventional drugs, including methotrexate.

[The non-recommendations in the treatment of osteoarthritis and rheumatoid arthritis, or why is evidence-based medicine so difficult (still) to apply to rheumatology?]. / Les non-recommandations dans le traitement de l'arthrose et de la polyarthrite rhumatoïde, ou pourquoi la médecine basée sur le niveau de preuve ne s'applique pas (encore) à la rhumatologie.

The speed with which the phrase "Evidence-Based Medicine" has entered our language has been astonishing. Virtually all medical areas are concerned, but it probably applies best when clearcut diagnosis can be made or when mortality or well-defined morbidity are the outcomes, two conditions not really frequently encountered in rheumatology. We will discuss why rheumatology is probably not ready yet for the concept and will systematically review why "Evidence-Based Medicine" could in fact be "evidence-biased medicine". We will emphasize why evidence-based medicine can not replace the personal experience and knowledge of patients, two major corner-stones in the clinician's daily work, but should simply be an access to scientific data for the benefit of both patient and physician.

[Etoricoxib (Arcoxia)]. / Le médicament du mois. Etoricoxib (Arcoxia).

Etoricoxib (Arcoxia) is a novel non steroidal anti-inflammatory drug (NSAID) that selectively inhibits the inducible form of cyclo-oxygenase (COX), COX-2. Etoricoxib has a higher COX-1/COX-2 selectivity ratio than the other COX-2-selective NSAIDs as rofecoxib, valdecoxib or celecoxib. Tablets of 60, 90 and 120 mg are available. The recommended dosage of etoricoxib is 60 mg/day for osteoarthritis, 90 mg/day for rheumatoid arthritis and 120 mg/day for acute gouty arthritis. Etoricoxib's efficacy has been widely studied in comparative studies, showing the same efficacy as non-COX-2 selective NSAID, with fewer gastro-intestinal adverse effects.

[Gout]. / La goutte.

In the presence of a clinical acute monoarthritis, a differential diagnosis has to be made between septic arthritis, gout and diffuse chondrocalcinosis. Gout comes from a purine nucleotide metabolism disorder leading to serum urate level elevation. This hyperuricemia can lead to the deposition of monosodium urate crystals in the joints, causing acute attacks. After long-term evolution, others tissues as the kidneys can be involved: it is chronic gout. The definite diagnosis is based on the presence of monosodium urate crystals in the joint fluid. The diagnosis of gout should prompt a search for associated medical conditions that may affect both urate levels and longevity. These include alcoholism, various nephropathies, myeloproliferative disorders, and hypertension.

[How I treat...rheumatoid arthritis. The arrival of a new therapeutic era: anti-tumor necrosis factor alpha antibodies]. / Comment je traite ... une polyarthrite rhumatoïde. L'avènement d'une nouvelle ère thérapeutique: les anticorps anti-TNF-alpha.

Rheumatoïd arthritis (RA) is the most frequent autoimmune inflammatory arthropathy. Chronic synovial inflammation usually results in cartilage destruction, bone erosion and subsequent joint deformities with impaired physical function. These consequences are more or less delayed by standard disease-modifying antirheumatic drugs (DMARDs). A better knowledge of the basic mechanisms of the disease and new biomolecular tools led to the development of novel biological agents including TNF alpha blockers. TNF alpha is a key inflammatory cytokine that plays a critically important role in the pathogenesis of RA. TNF alpha blockers brought dramatic improvements in efficacy of RA treatment. Here we will review the pathophysiological elements of RA wich explain the therapeutic efficacy of these TNF alpha blockers and we will describe in details the molecules, Remicade (Infliximab) and Enbrel (Etanercept), wich will be very soon used in daily practice in Belgium.