Rheumatoid Arthritis: France

Lioté H. · Service de Pneumologie et réanimation respiratoire, Hôpital Tenon, APHP, Paris, France. · Rev Mal Respir. · Pubmed #18971804 No free full text.

Abstract: INTRODUCTION: Lung disease is the most frequent and among the most severe extra-articular manifestation of rheumatoid arthritis (RA). Several interesting advances have been made in recent years in our understanding of this respiratory disease. STATE OF ART: 1. The induction of BALT responsible for follicular lymphoid infiltrates has been demonstrated in the wall of respiratory bronchioles. These lymphoid infiltrates are similar to synovial and skin cellular infiltrates and secrete specific markers of RA (citrullinated proteins). These data strongly suggest a common pathogenic mechanism for RA in the joints and in other sites, such as the lung. 2. Improvements in high resolution computed tomography (HR- CT) increased the sensitivity of diagnosis. CT evidence of pulmonary disease is present in 50% of RA patients, but only 10% of these patients have clinical symptoms. The different lung manifestations, frequently combined, have been clearly described: pulmonary nodules (20%); small airways disease (30%): bronchiolitis, bronchiolectasis, and bronchiectasis; diffuse interstitial pneumonia of various types (20%). 3. Predictors of progression and therapeutic response remain unknown. Therefore treatment is empirical and based on usual indications and on drugs used in idiopathic fibrosis and other connective tissue pulmonary pathologies. CONCLUSIONS: New biological drugs such as TNF blocking agents or anti CD20 antibody could be beneficial. Infections and drug-induced pneumonitis are not described in this review but must be considered systematically when an RA patient presents with lung involvement.

Fabien N, Goetz J, Sordet C, Humbel RL, Sibilia J, Anonymous00070. · Laboratoire d'auto-immunité, Hospices Civils de Lyon, Centre hospitalier Lyon-Sud, F-69495 Pierre Bénite Cedex, France. · Presse Med. · Pubmed #18951757 No free full text.

Abstract: New treatment strategies require that rheumatoid arthritis (RA) be diagnosed as early as possible. New diagnostic markers were required, because rheumatoid factors (RF), until now criteria for classification of RA, are not sufficiently specific and sometimes appear late, thereby limiting their diagnostic usefulness. The objective of this review is to describe the current state of knowledge and more particularly to analyze the interest of new RA autoanti-bodies, called anti-peptide or anti-citrullinated protein anti-bodies (ACPA). Other autoanti-bodies have been described, including anti-Sa, anti-alpha enolase, and anti-calpastatin autoanti-bodies. Nonetheless, their diagnostic value remains limited compared to ACPA. Accordingly, in daily practice today, the only autoanti-bodies that must be tested for to diagnose RA are the ACPAs and RFs. The discovery of ACPA (initially called anti-keratin and anti-perinuclear anti-bodies) was a major step forward for the laboratory diagnosis of RA. The tests most often used routinely areenzyme-linked immunosorbent assays(ELISA) with cyclic citrullinated peptides, whence the name anti-CCP autoanti-bodies. Accordingly, the two terms ACPA and anti-CCP can both be used. The diagnostic value, in particular their specificity, is on the order of 95%, regardless of the method of identification. These markers are very useful and are often present earlier than RF. These ACPA also have prognostic value because they are associated with more aggressive forms of RA. On the other hand, their value over time, in particular, their fluctuation as a function of treatment, is more controversial. In practice, it is recommended to test for both RF and ACPA in a diagnostic work-up for early RA. During follow-up, the value of testing for these autoanti-bodies has not been demonstrated, but additional studies are still necessary with the anti-CCP autoanti-bodies and the new anti-citrullinated protein autoanti-bodies.

Prey S, Paul C. · Department of Dermatology, Paul Sabatier University and Purpan Hospital, 31 059 Toulouse cedex 9, France. · Br J Dermatol. · Pubmed #18945303 No free full text.

Abstract: BACKGROUND: Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation. OBJECTIVES: We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate. METHODS: Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic. RESULTS: Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable. CONCLUSIONS: Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.

Larghero J, Vija L, Lecourt S, Michel L, Verrecchia F, Farge D. · Unité de thérapie cellulaire, Hôpital Saint-Louis, AP-HP, Paris, France. · Rev Med Interne. · Pubmed #18930338 No free full text.

Abstract: Mesenchymal stem cells (MSC) represent a population of the bone marrow microenvironment, which participates in the regulation of haematopoietic stem cells (HSC) self-renewal and differentiation. MSC are multipotent non-haematopoietic progenitors, which have been explored as a promising treatment in tissue regeneration. Both in vitro and in vivo, the MSC inhibit the T, B, NK and dendritic cell functions. Although MSC immunomodulating properties are not yet completely understood, their low immunogenic potential can be used as a therapeutic tool not only for regenerative medicine, but also for the treatment of graft-versus-host disease (GVHD) after bone marrow transplantation as well as for specific cases of severe refractory autoimmune diseases. Experimental and clinical data gave encouraging results, showing that MSC injection allowed controlling refractory GVHD, restoring bone development in children with osteogenesis imperfecta or improving heart function after myocardial infarction. Phase I-II studies are in progress in various countries to investigate the potential benefit from MSC due to their immunosuppressive properties, as an adjunctive therapy for severe refractory autoimmune disease.

Florea A, Job-Deslandre C. · Service de Rhumatologie A, Hôpital Cochin, AP-HP, Université Paris Descartes, Paris, France. · Presse Med. · Pubmed #18819772 No free full text.

Abstract: During pregnancy, oestrogen and progesterone levels are increased. Consequently the initial predominant immune cellular response (Th1 type) is decreased, whereas humoral response (Th2 type) is increased. Due to this switch, a lot of Th2 anti-inflammatory cytokines IL-4 and IL-10 are synthesized. During the last months of pregnancy Treg lymphocytes level is elevated leading to overexpression of IL-4 and IL-10. Due to these mechanisms, reduce disease activity of rheumatoid arthritis (RA) occurred. Impaired fertility has not been demonstrated in women with RA. However, some studies suggest that polyarthritis could induced a reduced weight at birth and more frequent pregnancy and delivery complications. Methotrexate and biotherapies have demonstrated no effect on fertility; however these drugs must be stopped before conception for a period equal to seven fold of the half live of the molecule. No teratogenic effect are known for sulfazalasine and hydroxychloroquine; these drugs could be used during pregnancy. It is also the same for ciclosporine, which used is quite unfrequent in RA. Methotrexate is teratogenic in animal models and is forbidden during pregnancy. For leflunomide which is metabolised in A771726, highly teratogenic, a washout period of 3,5 months is necessary. All commercially available TNFalpha inhibitors are classified by the food and Drug Administration as pregnancy risk category B: no adverse pregnancy adverse effects have been observed in animal studies, but there have been insufficient controlled human studies. The published experiences with TNFalpha inhibition in pregnancy is limited to some case reports and ongoing registry. More recently some cases of Vater syndromes (polymalformations) were possibly related to TNFalpha blocking agents. Such treatment must be avoided during pregnancy. Only few case reports are published concerning rituximab use during pregnancy. No data have been found for abatacept.

Harizi H, Corcuff JB, Gualde N. · Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5540, Immunomodulation par les Médiateurs de l'Inflammation, University of Bordeaux, 33076, France. · Trends Mol Med. · Pubmed #18774339 No free full text.

Abstract: Arachidonic acid (AA)-derived eicosanoids belong to a complex family of lipid mediators that regulate a wide variety of physiological responses and pathological processes. They are produced by various cell types through distinct enzymatic pathways and act on target cells via specific G-protein-coupled receptors. Although originally recognized for their capacity to elicit biological responses such as vascular homeostasis, protection of the gastric mucosa and platelet aggregation, eicosanoids are now understood to regulate immunopathological processes ranging from inflammatory responses to chronic tissue remodelling, cancer, asthma, rheumatoid arthritis and autoimmune disorders. Here, we review the major properties of eicosanoids and their expanding roles in biology and medicine.

Banal F, Dougados M, Combescure C, Gossec L. · Paris Descartes University, Medicine Faculty, Paris, France. · Ann Rheum Dis. · Pubmed #18728049 No free full text.

Abstract: OBJECTIVE: To evaluate the ability of the widely used ACR set of criteria (both list and tree format) to diagnose RA compared with expert opinion according to disease duration. METHODS: A systematic literature review was conducted in PubMed and Embase databases. All articles reporting the prevalence of RA according to ACR criteria and expert opinion in cohorts of early (<1 year duration) or established (>1 year) arthritis were analysed to calculate the sensitivity and specificity of ACR 1987 criteria against the "gold standard" (expert opinion). A meta-analysis using a summary receiver operating characteristic (SROC) curve was performed and pooled sensitivity and specificity were calculated with confidence intervals. RESULTS: Of 138 publications initially identified, 19 were analysable (total 7438 patients, 3883 RA). In early arthritis, pooled sensitivity and specificity of the ACR set of criteria were 77% (68% to 84%) and 77% (68% to 84%) in the list format versus 80% (72% to 88%) and 33% (24% to 43%) in the tree format. In established arthritis, sensitivity and specificity were respectively 79% (71% to 85%) and 90% (84% to 94%) versus 80% (71% to 85%) and 93% (86% to 97%). The SROC meta-analysis confirmed the statistically significant differences, suggesting that diagnostic performances of ACR list criteria are better in established arthritis. CONCLUSION: The specificity of ACR 1987 criteria in early RA is low, and these criteria should not be used as diagnostic tools. Sensitivity and specificity in established RA are higher, which reflects their use as classification criteria gold standard.

Boyer JF, Cantagrel A, Constantin A. · Larrey University Hospital, Rheumatology Department, 31059 Toulouse Cedex 9, France. · Curr Vasc Pharmacol. · Pubmed #18673161 No free full text.

Abstract: In chronic inflammatory diseases such as rheumatoid arthritis (RA), systemic inflammation appears as an independent risk factor, contributing to increased cardiovascular mortality. This high cardiovascular mortality reveals the existence of accelerated atherosclerosis, the pathogenesis of which may be associated with traditional risk factors such as smoking, hypertension, dyslipidemia, deterioration of insulin sensitivity, and less traditional risk factors such as hyperhomocysteinemia, inflammatory conditions and endothelial dysfunction. Control of systemic inflammation theoretically provides a means of preventing this higher cardiovascular mortality among RA patients. In this review we address the question of the impact of anti-rheumatic drugs currently used in RA, such as non-steroidal anti-inflammatory drugs (e.g. non-selective or cyclooxygenase-2 selective inhibitors), steroidal anti-inflammatory drugs (glucocorticoids), traditional disease-modifying anti-rheumatic drugs (e.g. methotrexate) or biologics (e.g. anti-tumour necrosis factor alpha anti-tumour necrosis factor alpha) on cardiovascular diseases in RA patients. We also discuss the specific mechanisms involved in the differential cardiovascular effects of these therapeutic agents.

Toussirot E, Pertuiset E, Kantelip B, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Besançon, France. · Clin Exp Rheumatol. · Pubmed #18578973 No free full text.

Abstract: Anti-TNF-alpha agents have been tried in cases of refractory sarcoidosis, giving favourable results. Thus, the occurrence of a granulomatous disease in a patient receiving such drug seems paradoxical. We describe 2 patients with inflammatory rheumatic disease, the first with ankylosing spondylitis, the second with rheumatoid arthritis, under anti-TNF-alpha treatment (infliximab and etanercept respectively) who developed non-caseating granulomas of the lungs and lymph nodes consistent with the diagnosis of sarcoidosis. Limited and various similar cases have been reported. It is generally considered that these granulomatous diseases are related to the anti-TNF-alpha agent.

Sibilia J, Gottenberg JE, Mariette X. · Service de Rhumatologie, CHU Strasbourg, Centre National de Référence des Maladies Auto-immunes Systémiques Rares, Strasbourg, France. · Joint Bone Spine. · Pubmed #18571968 No free full text.

Abstract: Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B cells, which play numerous pathogenic roles in rheumatoid arthritis (RA). This review summarises the results of three controlled studies using rituximab in RA and the data regarding tolerance and repeated treatment in 1053 patients included in the clinical studies. These studies demonstrated the efficacy of rituximab in patients with RA, including those who had been unresponsive or intolerant to one or more TNF inhibitor therapies. Rituximab was globally well-tolerated. The current informations on the efficacy and the tolerance of rituximab led us to propose recommendations for the screening of patients, the use of rituximab, and the follow-up of patients. A longer follow-up duration and data from off-trial patients, included in registries, are now required.

Zouali M. · Inserm, U606, Paris, F-75475 France. · Front Biosci. · Pubmed #18508550 No free full text.

Abstract: For some time, B cells have been considered as passive actors, exclusively depending on T cell conductors that provide them with instructions to engage in antibody secretion. With further investigation, however, it became evident that B cells can exert a number of antibody-independent functions, capturing and concentrating antigen for presentation, producing cytokines, influencing T cell and dendritic cell responses, contributing distinct functions during the immune response, affecting lymphoid tissue structures, and, even participating in tissue repair. Because of their multiples functions, B cells are currently recognized to play a key role in a variety of antibody-, and T cell-mediated autoimmune diseases, including lupus, rheumatoid arthritis, type-1 diabetes and multiple sclerosis. This recent insight led to novel immuno-intervention strategies that target B cells, with beneficial effects in patients. While such novel therapeutic bio-drugs are being introduced into the clinical arena, research intensifies in order to identify novel targets and strategies whose ultimate goal is to knock out specifically pathogenic B cells, and to amplify the numbers and the activity of cells endowed with regulatory functions.

Laharie D, Terrebonne E, Vergniol J, Chanteloup E, Chabrun E, Couzigou P, de Lédinghen V. · Centre d'investigation de la fibrose hépatique, hôpital Haut-Lévêque, 33604 Pessac cedex, France. · Gastroenterol Clin Biol. · Pubmed #18494155 No free full text.

Abstract: Methotrexate is proposed for the treatment of inflammatory disorders such as rheumatoid arthritis, psoriasis and Crohn's disease. The liver toxicity of methotrexate has been investigated and prolonged treatment can induce liver fibrosis. Moreover, alcohol consumption, diabetes and obesity are associated with liver fibrosis in patients treated with this drug. Therefore, liver fibrosis associated with methotrexate could be due to associated factors instead of methotrexate itself. Recommendations to monitor and diagnose methotrexate induced liver damage vary depending on the disease. Frequent evaluation of liver fibrosis with liver biopsy is recommended during therapy, especially in patients treated for psoriasis. Noninvasive methods, such as the FibroScan, could be useful for the assessment of liver fibrosis associated with methotrexate and hence, need further evaluation.

Bannwarth B. · Department of Rheumatology, Pellegrin Hospital and Division of Therapeutics, Victor Segalen University, Bordeaux, France. · Drug Saf. · Pubmed #18484783 No free full text.

Abstract: Although effective in the treatment of pain associated with rheumatic conditions such as osteoarthritis and rheumatoid arthritis, long-term use of NSAIDs is primarily limited by their association with upper gastrointestinal (GI) toxicity. Adverse effects range from dyspepsia and abdominal pain to ulceration and bleeding. GI damage elicited by NSAIDs arises as the result of biochemically induced topical irritant effects and by topical and systemic pharmacological suppression of gastroprotective prostaglandins. Variation in the physicochemical properties and pharmacological profiles among the individual NSAIDs translate into inter-agent differences regarding propensity to cause adverse GI effects. Nabumetone is a nonselective NSAID that offers distinct advantages over other agents in this class with regard to GI tolerability. Its non-acidic nature and pro-drug formulation, together with the lack of biliary secretion of its active metabolite, 6-methoxy-2-naphthylacetic acid, are thought to contribute to the improved GI tolerability of this drug. In head-to-head trials with other NSAIDs, nabumetone has demonstrated significant benefits regarding the incidence of GI events and more serious perforations, ulcers and bleeds (PUBs). Pooled data from eight postmarketing, randomized, controlled trials demonstrated a lower cumulative frequency of PUBs with nabumetone (0.03%; 95% CI 0.0, 0.08) versus comparator NSAIDs (1.4%; 95% CI 0.5, 2.4). Large-scale database studies also indicate that risk of serious GI complications is lower with nabumetone than comparator NSAIDs. Limited comparative data suggest that nabumetone offers a GI tolerability profile similar to that of cyclo-oxygenase-2 selective NSAIDs (coxibs). Although adverse cardiovascular outcomes appear to be a class effect of the coxibs, conventional NSAIDs may also have the potential for causing atherothrombotic complications. However, based on available data, nabumetone does not appear to be associated with increased cardiovascular risk. Finally, there is no particular concern about the nephrotoxic and hepatotoxic potential of nabumetone. Nonetheless, the potential for adverse drug reactions remains, and hence nabumetone, as with any NSAID, should be used at the lowest dose, which is effective for each patient, and for the shortest time necessary to control symptoms.

Jorgensen C, Djouad F, Bouffi C, Mrugala D, Noël D. · Inserm U844, CHU Saint Eloi, Bâtiment INM, 80 avenue Augustin Fliche, Montpellier F-34091, France. <> · Best Pract Res Clin Rheumatol. · Pubmed #18455684 No free full text.

Abstract: Although cartilage defects are common features of osteoarthritis and rheumatoid arthritis, current treatments can rarely restore the full function of native cartilage. Recent studies have provided new perspectives for cartilage engineering using multipotent mesenchymal stromal cells (MSC). Moreover, MSC have been used as immunosuppressant agents in autoimmune diseases and have tested successfully in animal models of arthritis. However, the sequential events occurring during chondrogenesis must be fully understood before we can reproduce the complex molecular events that lead to MSC differentiation and long-term maintenance of cartilage characteristics in the context of chronic joint inflammation. This chapter focuses on the potential of MSC to repair cartilage, with an emphasis on the factors that are known to be required in inducing chondrogenesis and on their immunosuppressive potential.

Pertuiset E. · Service de rhumatologie, centre hospitalier René-Dubos, 6, avenue de l'Ile-de-France, B.P. 79, Pontoise, 95303 Cergy-Pontoise cedex, France. · Rev Med Interne. · Pubmed #18433944 No free full text.

Abstract: PURPOSE: Spondyloarthritis (SpA) encompass different diseases with common characteristics, ankylosing spondylitis (AS) being the most typical. Undifferentiated SpA may evolve into AS. In France, SpA and rheumatoid arthritis could have the same prevalence. AS has a profound impact on the quality of live and function of patients as well as social and economic consequences for the society. KEY POINTS: There is a mean delay of five to eight years between onset of symptoms and diagnosis of AS. This is due to the fact that radiographic sacroiliitis is delayed. The purpose of an earlier diagnosis is emphasized by the need for a better management, the new diagnostic method including magnetic resonance imaging and ultrasonography, and by the efficacy of anti-TNF therapy. The current criteria (New-York, Amor, ESSG) are classification but not diagnostic criteria. Their sensitivity is insufficient for an early diagnosis of SpA. Several groups are studying methods to ensure an early diagnosis. The group of Berlin has proposed, for patients suffering inflammatory chronic back pain, an algorithm using clinical, radiological and biological signs with, if necessary, search of HLA-B27 and MRI of sacroiliac joints. But this system is theoretical and the group of Maastricht found it of little effectiveness. Furthermore, it does not take account patients with symptoms beginning out of the spine. CONCLUSION: We believe that only the follow-up of cohorts constituted of patients with early SpA will enable us to improve our knowledge regarding diagnostic criteria and new tools for early diagnosis, as well as outcome, prognosis and early management of SpA and AS.

Avouac J, Allanore Y. · Paris Descartes University, Medical Faculty, Department of Rheumatology A, Cochin Hospital, AP-HP, Paris, France. · Expert Opin Pharmacother. · Pubmed #18422470 No free full text.

Abstract: BACKGROUND: Patients with rheumatoid arthritis (RA) have an increased risk of atherosclerotic cardiovascular disease which cannot be explained by traditional cardiovascular risk factors alone. Atherosclerosis is considered an inflammatory condition and inflammation experienced in RA may contribute to accelerated atherosclerosis. Thus, it should be hypothesized that treatment with antitumor necrosis factor alpha (anti-TNF-alpha), TNF-alpha being a pivotal component of the inflammatory cascade, may decrease concomitantly intra-articular inflammation and vessel inflammation. OBJECTIVE: The purpose of this review is to examine the data regarding cardiovascular mortality and morbidity in RA and the evidence available to date evaluating the influence of anti-TNF-alpha treatments in RA on the occurrence of cardiovascular events, on surrogate markers of atherosclerosis and classical cardiovascular risk factors. METHODS: Clinical trials, original studies and review articles were identified from a Medline search (1998 - December 2007). Articles in English were reviewed, with emphasis on those containing assessments of cardiovascular effects (i.e., biological, structural, clinical) of anti-TNF-alpha drug. CONCLUSION: The suppression of systemic inflammation favoring atherosclerosis may lead to an improvement in cardiovascular prognosis in inflammatory disorders. Thus, reduction of inflammatory joint disease in RA with anti-TNF-alpha therapy, as probably with any powerful disease-modifying antirheumatic drugs, seems to be, at least in part, associated with concomitant reduction of the risk of cardiovascular events.

Hallett JM, Leitch AE, Riley NA, Duffin R, Haslett C, Rossi AG. · MRC Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh EH16 4TJ, UK. · Trends Pharmacol Sci. · Pubmed #18407359 No free full text.

Abstract: Resolution of inflammation requires the effective downregulation of key inflammatory cells such as neutrophils and eosinophils, which normally undergo programmed cell death (apoptosis) to enable their detection and removal by phagocytes such as macrophages. Dysregulation of this process is thought to contribute to the pathogenesis and progression of chronic inflammatory disorders such as chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, allergic rhinitis and inflammatory bowel disease. Importantly, knowledge of the signalling pathways responsible for the induction and execution of granulocyte apoptosis and the phagocytic removal of apoptotic cells continues to increase and, with it, the potential for incisive pharmacological intervention. In this article, we highlight pharmacological strategies that could be used to drive the resolution of inflammation by augmenting apoptosis of inflammatory cells.

Pers JO, Le Pottier L, Devauchelle V, Saraux A, Youinou P. · Laboratoire d'immunologie, centre hospitalier universitaire de Brest, B.P. 824, 29609 Brest, France. · Rev Med Interne. · Pubmed #18403061 No free full text.

Abstract: INTRODUCTION: Sjögren's syndrome (SS) is an autoimmune epithelitis hallmarked by a disruption of epithelial cells, the subsequent lymphocytic infiltration of lachrymal and salivary glands (SGs), and their ensuing dryness. One may posit that SS is triggered by viruses, and/or modulated by sex steroid hormones, and there is indeed a consensus that its aetiology is multifactorial, with genetic factors interacting with environmental agents. CURRENT KNOWLEDGE AND KEY POINTS: T-cells have long occupied central stage of the debate on the type of lymphocytes involved in the pathogenesis of SS. The relevance of B cells has, however, been emphasized over the past five years and new insights into their functions revealed. Furthermore, increased levels of the B-cell activating factor (BAFF) may be responsible for quantitative and qualitative anomalies of B-cells found in SS such as emergence of self reactive B-cells. This review reports compelling evidence that B-cells are involved in the pathophysiology of SS. PROSPECTS: Since SS may thus be conceived as a model for B-cell-induced autoimmunity, it is no surprise that B-cell ablative-treatment has proven to be relatively effective in SS.

Kalyoncu U, Dougados M, Daurès JP, Gossec L. · Paris Descartes University, Medicine Faculty, Paris, France. · Ann Rheum Dis. · Pubmed #18375533 No free full text.

Abstract: OBJECTIVES: Patient-reported outcomes (PROs) have been increasingly recognised as important in rheumatoid arthritis (RA). The objective of this study was to assess the frequency of use of different PROs in recently published RA articles and to compare the tools used through a systemic literature review. METHODS: (1) DATA SOURCE: In PUBMED MEDLINE database, articles reporting any type of clinical study for adult patients with RA, published between February 2005 and February 2007, and reporting any type of PRO. Articles were excluded if they did not concern adult RA or if they did not report any PROs. (2) DATA EXTRACTION: demographic characteristics of patients, study design, treatment assessed and all PROs. (3) Data analysis: descriptive. RESULTS: Of 109 reports, 50 (45%) were randomised controlled trials and 59 were other types of studies. A total of 63 questionnaires or tools for PROs were used, corresponding to 14 domains of health. Frequently reported domains (and most frequent tools) were: function, 83% (most frequent tool, health assessment questionnaire, HAQ); patient global assessment, 61% (most frequent tool, visual analogue scale, VAS); pain, 56% (VAS); and morning stiffness 27%. Domains such as fatigue, coping or sleep disturbance were infrequently reported. CONCLUSIONS: PROs are reported with great heterogeneity in recently published trials in RA. Some domains that appear important from the patient's perspective are infrequently reported. Further work is needed in this field.

Bensussan A, Bizzini B, Pouletty P, Gallo RC, Zagury D. · Institut National de la Santé et de la Recherche Médicale, Inserm U841, Créteil, France. · Med Sci (Paris). · Pubmed #18334181 No free full text.

Abstract: The abnormal cytokine release in the stromal microenvironment of pathologic tissues, contributes to the pathogenesis of viral infections such as AIDS, cancer and auto-immune diseases. Neovacs developed therapeutic vaccines, named Kinoids, which induce anti-cytokine Antibodies. Kinoids are non toxic but immunogenic cytokine derivatives. Kinoid immunizations induce high titre of neutralizing Abs to the corresponding cytokine, is well tolerated and experimentally effective. In transgenic mice expressing huTNFalpha, the TNFalpha kinoid decreases clinical signs of Rheumatoid Arthritis and in mice challenged with syngenic CT26 tumor cell line huVEGF kinoid inhibits lung metastases. After validation by clinical trials, kinoid vaccines could represent a second generation of specific immune therapy to be used to combat ectopic cytokines.

Cottin V. · Service de pneumologie, centre de référence des maladies orphelines pulmonaires), hôpital Louis-Pradel, hospices civils de Lyon, université Lyon-I, université de Lyon, UMR 754 INRA-ENVL-UCBL-IFR128, 69677 Lyon, Bron. · Rev Prat. · Pubmed #18320743 No free full text.

Abstract: Interstitial lung disease (ILD) may occur in the connective tissue diseases, with a negative impact on survival. The diagnosis of ILD is established by crackles of the lung bases at auscultation, and high resolution computed tomography of the chest demonstrating diffuse opacities predominating in the bases (ground glass opacities, reticular opacities, honeycombing, and traction bronchiectases). Bronchoalveolar lavage mostly contributes to the differential diagnosis. Video-assisted thorascopic lung biospy is seldom required for clinical management. Clinically significant ILD occurs in 25% of patients with systemic sclerosis, 7-30% in patients with dermatopolymyositis (especially with antisynthetase antibodies including anti-Jo-1 antibodies, often with a subacute onset), and 5% of patients with rheumatoid arthritis. Nonspecific interstitial pneumonia (with fibrosis) is the predominating histopathological pattern in systemic sclerosis and dermatopolymyositis; a pattern of usual interstitial pneumonia is frequent in rheumatoid arthritis (with a clinical and radiological presentation similar to that of idiopathic pulmonary fibrosis). ILD of various presentations may occur in Sjögren syndrome, possibly associated with thin-walled cysts; pulmonary lymphoma must be ruled out. Little information is available regarding treatment of ILD in connective tissue disease. Clinically modest short-term efficacy of cyclophosphamide treatment has been shown in systemic sclerosis, but was not maintained at 2 years.

Avouac J, Uzan G, Kahan A, Boileau C, Allanore Y. · Rheumatology A department, René Descartes University, Cochin Hospital, APHP, 27 rue du faubourg Saint-Jacques, 75014 Paris, France. · Joint Bone Spine. · Pubmed #18314371 No free full text.

Abstract: In human adults, new blood vessels may form via endothelial sprouting from pre-existing endothelial cells/angioblasts (angiogenesis) or via the recruitment of circulating endothelial progenitor cells (EPCs) (vasculogenesis). EPCs are a population of bone marrow-derived cells able to differentiate into mature endothelial cells and participating in the formation of new blood vessels. The molecular phenotype of EPCs and processes leading to their mobilization from bone marrow and homing to neovascularization sites remain unclear. There is still debate regarding methods for their quantification and isolation. In the field of rheumatology, EPCs have been studied in multiple myeloma and inflammatory rheumatic disorders. In myeloma, data suggest that EPCs could be reliable biomarkers of tumor angiogenesis, growth and antiangiogenic therapy efficacy. Recent studies suggest that EPCs are involved in synovial vascularization, and may contribute to the increased cardiovascular morbidity and mortality in rheumatoid arthritis, known features of this disease. In systemic lupus erythematosus, preliminary data suggest that EPCs are decreased. Results available in systemic sclerosis are consistent with the hypothesis that EPCs are recruited during active disease; however, their levels may be depleted as the disease progresses and under chronic ischemic conditions. EPCs are important in vasculogenesis, and may be involved in other systemic features of inflammatory rheumatic disorders.

Salliot C, Dougados M, Gossec L. · René-Descartes University, Medicine Faculty, AP-HP, Cochin Hospital, Rheumatology B Department, Paris, France. · Ann Rheum Dis. · Pubmed #18203761 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor alpha blockers in rheumatoid arthritis are known to increase the risk of serious infections defined as life-threatening, requiring hospitalisation or intravenous antibiotics. Recently, new biological agents have become available. Their safety is an important issue. PURPOSE: To assess if biological agents, ie rituximab, abatacept and anakinra increase the risk of serious infections in patients with rheumatoid arthritis in published randomised controlled trials. DATA SOURCE: A systematic review of the literature using PUBMED, EMBASE, Cochrane library and abstracts databases (American College of Rheumatology and European League Against Rheumatism annual meetings) was performed up to October 2007. This search was completed with data from the Food and Drug Administration, the European Agency for the Evaluation of Medicinal Products and manufacturers. DATA EXTRACTION: Three fixed-effect meta-analyses were performed to compare serious infection rates between each biological agent and placebo. Pooled odds ratios (ORs) were calculated, using the Mantel-Haenszel method with a continuity correction. DATA SYNTHESIS: Twelve randomised controlled trials with data concerning serious infections were analysed (three for rituximab, five for abatacept and four for anakinra). They included 745 patients, 1960 patients, 2062 patients and 2112 patients treated by rituximab, abatacept, anakinra and placebo respectively. The overall pooled ORs did not reveal a statistically significant increased risk of serious infection for abatacept and rituximab; this risk was increased for high doses of anakinra (> or =100 mg daily) versus low dose and placebo (ORs = 9.63 (95% CI, 1.31 to 70.91) and 3.40 (95% CI, 1.11 to 10.46) respectively). CONCLUSIONS: These meta-analyses did not reveal a significant increase in the risk of serious infections during rituximab or abatacept treatments in patients with rheumatoid arthritis; however, high doses of anakinra may increase this risk, especially when patients have comorbidity factors. Large studies must be performed to confirm this safety profile in daily practice.

Simon D. · Service d'Endocrinologie Pédiatrique, Hôpital Robert Debré, Paris, France. · Horm Res. · Pubmed #18174727 No free full text.

Abstract: BACKGROUND: Inflammation and glucocorticoid therapy are major factors in the growth retardation seen in children with severe forms of juvenile idiopathic arthritis (JIA). It has been recently shown that tumor necrosis factor (TNF)-alpha antagonist therapy can improve growth velocity in JIA patients; however, the recombinant human soluble TNF-alpha receptor fusion protein etanercept has had limited efficacy in systemic forms of JIA. For several years, growth hormone (GH) has been used to treat growth retardation in patients with JIA receiving glucocorticoids. GH treatment can normalize growth velocity and prevent the severe loss of height; however, catch-up growth markedly varies with the severity of the inflammatory state and the steroid doses used during GH treatment. Recently, early institution of GH treatment has been shown to maintain normal growth in children with JIA. CONCLUSIONS: These promising results show the need for careful monitoring of growth in children with JIA, the utility of GH therapy before the onset of severe growth delay and the potential for preservation of long-term growth during disease progression.

Kobelt G, Jönsson B. · Department of Orthopedics, University of Lund, Lund, Sweden. · Eur J Health Econ. · Pubmed #18157559 No free full text.

Abstract: Within the series of articles investigating the burden of rheumatoid arthritis (RA), this paper reviews the methods used for economic assessment of the RA treatments by HTA agencies and other bodies involved in cost-effectiveness analysis and the current status of the field. The overall methods, as well as the challenges, of cost-effectiveness analysis in RA are common to all chronic progressive diseases where much of the treatment benefit is delayed, while costs occur immediately. Also, as in all disabling diseases, much of the costs occur outside the health-care system, due to the rapid loss of work capacity and the need for informal care in the later stages of the disease. Thus, it is essential to adopt a long-term view and consider costs from the perspective of society, rather than the health-care service, to increase the relevance of the results for policy making.