Rheumatoid Arthritis: Mariette X

Pham T, Fautrel B, Gottenberg JE, Goupille P, Hachulla E, Masson C, Morel J, Mouthon L, Saraux A, Schaeverbeke T, Wendling D, Mariette X, Sibilia, Anonymous00011. · No affiliation provided · Joint Bone Spine. · Pubmed #18708020 No free full text.

This publication has no abstract.

Fautrel B, Pham T, Mouterde G, Le Loët X, Goupille P, Guillemin F, Ravaud P, Cantagrel A, Dougados M, Puéchal X, Sibilia J, Soubrier M, Mariette X, Combe B, Anonymous00061, Anonymous00062. · Pierre and Marie Curie University - Paris VI, UFR de Médecine, France. · Joint Bone Spine. · Pubmed #18037319 No free full text.

Abstract: OBJECTIVES: To update French Society for Rheumatology guidelines regarding the use of TNFalpha antagonists for treating patients with rheumatoid arthritis (RA). METHODS: Existing guidelines were updated using the AGREE instrument. Items that required updating were selected by a task force, the relevant literature was critically appraised, and new wording was suggested by a limited committee of experts then validated by the task force and subsequently by a panel of external reviewers. The three-topic structure of the recommendations (indication, initiation, and adjustment) and the final algorithm format were maintained. RESULTS: Of the 12 items, five were selected for updating; one pertained to the indication for treatment with TNFalpha antagonists, two to treatment initiation, and two to treatment adjustment. Of the four initially recommended criteria for determining that TNFalpha antagonist therapy is indicated, the first three were left unchanged (confirmed diagnosis of RA; active disease for more than 1month with objective evidence of inflammation or progressive structural damage, or dependency on glucocorticoid therapy, or progressive radiographic damage; and failure to respond adequately to methotrexate - or another agent when methotrexate is contraindicated - in the optimal tolerated dosage). The fourth and last criterion was modified as follows: co-morbidities should be evaluated in order to distinguish absolute contraindications from relative contraindications that require referral to a specialist. Of the four initial recommendations about TNFalpha antagonist initiation, the first and fourth were left unchanged (a workup should be performed prior to treatment initiation, and the patient should receive regular standardized follow-up); the second and third recommendations were modified as follows: there is no evidence that one TNFalpha antagonist is more effective than the others, and concomitant methotrexate therapy is generally advisable, regardless of the TNFalpha antagonist used. Of the four recommendations about treatment adjustment, the first two were modified as follows: the goal of treatment is to achieve the EULAR response criteria or better; and in non-responders, the dosage or dosing interval can be modified when infliximab is used, methotrexate should be added when the TNFalpha antagonist is used alone, and in all other situations the patient should be switched to a different TNFalpha antagonist. The other two recommendations about treatment adjustment were left unchanged (patients who fail to tolerate one TNFalpha antagonist can be switched to another TNFalpha antagonist if allowed by the nature of the adverse event; and when a remission is achieved, reduction or discontinuation of symptomatic drugs - most notably glucocorticoids - is appropriate, followed in the event of a prolonged remission by changes in the dosage and/or dosing interval of the TNFalpha antagonist or concomitant disease-modifying drug). CONCLUSION: These recommendations are designed to help practitioners optimize the use of TNFalpha antagonists in patients with RA seen in everyday practice. They do not constitute regulations.

Mariette X. · No affiliation provided · Joint Bone Spine. · Pubmed #15474382 No free full text.

This publication has no abstract.

Mariette X. · Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Université Paris-Sud 11, Le Kremlin Bicêtre, Institut Pour la Santé et la Recherche Médicale (INSERM) U 802, France. · Rheum Dis Clin North Am. · Pubmed #18984420 No free full text.

Abstract: B-cell hyperactivity has been recognized for a long time in Sjögren's syndrome. This B-cell activation is firstly polyclonal but can progress to monoclonal B-cell lymphoproliferation. This article addresses the therapeutic potential of B-cell modulation in Sjögren's syndrome.

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.

Miceli-Richard C, Comets E, Verstuyft C, Tamouza R, Loiseau P, Ravaud P, Kupper H, Becquemont L, Charron D, Mariette X. · Rhumatologie, Institut Pour la Santé et la Recherche Médicale U 802, Université Paris-Sud 11, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #17673491 No free full text.

Abstract: OBJECTIVE: To determine whether tumour necrosis factor (TNF) gene polymorphisms and/or the shared epitope are genetic predictors of the response to adalimumab (ADA) in rheumatoid arthritis (RA). METHODS: This ancillary study to the Research in Active Rheumatoid Arthritis (ReAct) Phase IIIb study included a large cohort of Caucasian patients with RA from France (n = 388) treated with ADA plus methotrexate (MTX) (n = 182), ADA plus any other DMARD (n = 98) or ADA alone (n = 108). The primary outcome was ACR50 at 12 weeks. Patients underwent genotyping for HLA-DRB1 and three TNF gene polymorphisms (-238A/G,-308A/G and-857C/T). Extended haplotypes involving HLA-DRB1 and TNF loci were reconstructed using the PHASE program. RESULTS: A total of 151 patients (40%) had an ACR50 response at week 12. Neither the number of HLA-DRB1 shared epitope copies nor presence of the three TNF polymorphisms tested separately was significantly associated with ACR50 response at week 12. However, haplotype reconstruction of the TNF locus revealed that the GGC haplotype (-238G/-308G/-857C) in a homozygous form (i.e. present in more than half of the patients) was significantly associated with a lower ACR50 response to ADA at 12 weeks (34% vs. 50% in patients without the haplotype) (p = 0.003; pa = 0.015). This effect was more important in the subgroup of patients concomitantly treated with MTX. CONCLUSION: This large pharmacogenetic study provides preliminary data indicating that a single TNF locus haplotype (-238G/-308G/-857C), present on both chromosomes is associated with a lower response to ADA, mainly in patients treated with ADA and MTX.

Salliot C, Mouthon L, Ardizzone M, Sibilia J, Guillevin L, Gottenberg JE, Mariette X. · Rheumatology Department, Paris-Sud 11 University, INSERM U802, France. · Rheumatology (Oxford). · Pubmed #16877466 links to  free full text

Abstract: OBJECTIVES: When Sjögren's syndrome (SS) is secondary to rheumatoid arthritis, the sicca syndrome is less serious and anti-SSA/SSB antibodies are found less frequently than in primary SS (pSS). When SS is associated with systemic lupus erythematosus, clinical and serological patterns are similar to those of pSS. We aimed to determine whether SS, accompanying systemic sclerosis (SSc), could be considered secondary to or associated with SSc and whether the coexistence of both modifies the severity and the outcome of each disease. Patients and METHODS: A retrospective multicentric study was conducted to compare (i) characteristics and complications of SS between 27 patients with SS and SSc (SS-SSc) and 202 patients with pSS, and (ii) the characteristics of SSc and complications between the SS-SSc group and 94 patients with SSc alone. RESULTS: SS features were similar in both SS-SSc and pSS patients, except for peripheral neuropathy and arthritis, which was more common in SS-SSc than in the pSS patients (P = 0.02 and 0.05, respectively). SSc appears to be less severe in patients with SS-SSc than SSc alone with a lower frequency of lung fibrosis (P = 0.05). Compared with patients with pSS or SSc alone, SS-SSc patients were more likely to have another autoimmune disorder and other autoantibodies (SS-SSc vs pSS, P = 0.02 and P = 0.03, respectively). CONCLUSION: SS seems to be associated with and not secondary to SSc. SS associated with SSc has the same features as pSS, but SSc seems to be less serious. Moreover, the association of SS and SSc is frequently accompanied by a spreading of autoimmunity.

Picone O, Alby C, Frydman R, Mariette X. · Service de Gynécologie Obstétrique, Hôpital Antoine-Béclère, 157, rue de la Porte-de-Trivaux, 92140 Clamart. · J Gynecol Obstet Biol Reprod (Paris). · Pubmed #16575363 links to  free full text

Abstract: Sjogren syndrome (SS) is an immune disease characterized by a progressive degeneration of exocrine glands. It leads to dryness of mucosa and conjunctivitis. Gynecologists and obstetricians may encounter this disease in women at any age, including during pregnancy. Knowledge of the main characteristics is required for early diagnosis and multidisciplinary program. In the event of secondary Sjögren syndrome occurring during pregnancy, treatment focuses on the associated disease, mainly systemic lupus erythematosus. In primary Sjögren syndrome, pregnancy does not appear to influence disease course. However, patients with both primary and secondary Sjögren syndrome must be monitored carefully. There is a risk of neonatal lupus and congenital atrioventricular bloc associated with high morbidity and mortality. These patients should benefit from multidisciplinary care in a hospital with a neonatal intensive care unit.

Fautrel B, Pham T, Gossec L, Combe B, Flipo RM, Goupille P, Le Loët X, Mariette X, Puéchal X, Wendling D, Schaeverbeke T, Sibilia J, Sany J, Dougados M. · Service de rhumatologie, groupe hospitalier Pitié-Salpêtrière, Paris, France. · Joint Bone Spine. · Pubmed #15797498 No free full text.

Abstract: OBJECTIVES: To develop recommendations for the information and education of patients with rheumatoid arthritis (RA) seen in everyday practice, using evidence from the literature, supplemented with expert opinion when needed. METHODS: A scientific committee developed eight questions using the Delphi consensus procedure. A task force reviewed the literature for answers to these questions, using the PubMed Medline database (1980-2004) and the 2002-2004 databases of the annual meetings held by the French Society for Rheumatology (SFR), the European League Against Rheumatism (EULAR), and the American College of Rheumatology (ACR); the indexing terms for the search were rheumatoid, arthritis, patient, education, information, knowledge, general practitioner, family doctor, and continuing medical education. Only articles in French or English were included. A panel of rheumatologists used the evidence thus compiled to develop recommendations for each question; gaps in evidence were filled by calling on the panelists' expert opinion. For each recommendation, the level of evidence and extent of agreement among panelists were specified. RESULTS: There were four general questions about the objectives, supports, and mode of delivery (group or one-on-one) of patient information and education, as well as on evaluating knowledge, and four specific questions on program content. The search identified 1235 articles; 144 were selected on the title and 118 of those on the abstract. Three abstracts presented at meetings were also kept. The evidence from the literature was presented to the panelists during interactive workshops. The panelists then developed eight recommendations, all of which were grade D because no published studies specifically addressed everyday clinical practice. Agreement among panelists ranged across recommendations from 85.7% to 100%. CONCLUSION: Recommendations about educating and informing patients with RA in everyday practice were developed. They should increase practice uniformity and ultimately optimize the management of patients with RA.

Mariette X. · Rheumatology Department, Inserm EMI 109, Bicêtre Teaching Hospital, Paris-Sud University, Le Kremlin Bicêtre, France. · Joint Bone Spine. · Pubmed #15589425 No free full text.

Abstract: The introduction of TNFalpha inhibitors has radically changed the management of patients with refractory rheumatoid arthritis (RA) or spondyloarthropathy. However, among patients with RA unresponsive to methotrexate, only two-thirds respond to TNFalpha inhibitors. Fortunately, more than 5 years after infliximab was introduced on the market, preliminary evidence that emerging biological agents are effective is beginning to accumulate, generating new hope for patients who fail to respond to TNFalpha inhibitors. These novel biological therapies grew out of original pathophysiological hypotheses, a fact that vividly illustrates the importance of basic pathophysiological research for developing new medications. This review provides detailed information on three biological therapies whose efficacy in RA was demonstrated in recently published randomized placebo-controlled trials: a monoclonal antibody to the IL-6 receptor (MRA), CTLA4-Ig (abatacept), and a monoclonal B-cell-specific antibody to CD20 (rituximab). Good risk/benefit ratios seem to be achieved with MRA alone or with abatacept or rituximab combined with methotrexate. However, as yet, no radiographic data are available for these treatments. One of the challenges for the future is to identify ingenious combinations of biological therapies capable of improving the quality and duration of responses without exacerbating side effects.

Mariette X. · Service de rhumatologie, hôpital de Bicêtre, Assistance publique-Hôpitaux de Paris, université Paris-Sud, Le Kremlin-Bicêtre, France. · Rev Med Interne. · Pubmed #15112663 No free full text.

Abstract: PURPOSE: In Sjögren's syndrome (SS), oral dryness is frequently the most bothersome symptom of sicca syndrome with negative affects on quality of life. A review of treatments of oral dryness is proposed. CURRENT KNOWLEDGE AND KEY POINTS: To date, so specific DMARD has demonstrated its efficacy in SS. Hydroxychloroquine is frequently used but did not demonstrate any clinical benefit in te only small randomized control study versus placebo available. Thus, the only treatments are symptomatic. The most recent data show that systemic cholinergic agonist (pilocarpine and cevimeline) are effective in the symptomatic treatment of dryness. Pilocarpine (Salagen) is the only systemic cholinergic agonist available in Europe. It has been agreed in France since July 2003. FUTURE PROSPECTS AND PROJECTS: Use of immunosuppressive drugs may be useful in some complications of SS. Unfortunately, promising results from an open study with infliximab (Remicade) were not confirmed by a large randomized control study involving more than 100 patients. New control studies with old drugs such as hydroxychloroquine, or new ones such as rituximab, are mandatory.

Mariette X. · Service de Rhumatologie, Hôpital de Bicêtre, AP-HP, 94275 Le Kremlin-Bicêtre. · Ann Med Interne (Paris). · Pubmed #12910042 No free full text.

Abstract: Sjögren's syndrome (SS) is an excellent model for understanding the pathophysiology of autoimmune diseases and the relationships between autoimmunity and lymphoma. Recently discovered new elements probably play a role in the pathogenesis of this multifactorial disease: genetic predisposition remains largely unknown, but there isa link between certain HLA molecules and the type of autoantibodies secreted; sometimes called autoimmune epithelitis, SS is associated with abnormal apoptosis activity in epithelial cells leading to an abnormal accumulation of degradation products of the cytoskeleton proteins such as alpha- and beta-fordrine and also to the presentation of numerous antinuclear autoantigens to the immune system; significant polyclonal activation of B lymphocytes is probably mediated, at least in part, by a major increase in molecules of the TNF family (e.g. BlyS or BAFF) which play an important role in the production of autoantibodies; cytokine inhibition of healthy glands or anti-muscarin receptor antibodies and abnormal function of certain water pumps such as aquaporine could explain the perturbed function of the remaining healthy glands; permanent stimulation of autoreactive B cells favors oncogenic events and could lead to the development of B lymphoma with autoantibody activity. The links between these different elements are progressively falling into place. A better understanding of the pathophysiology of SS can be expected to lead to the development of much needed new therapeutic tools.

Mariette X. · Service de rhumatologie Hôpital de Bicêtre 94275 Le Kremlin-Bicêtre. · Rev Prat. · Pubmed #12722608 No free full text.

Abstract: Tumour necrosis factor (TNF) alpha and interleukine 1 (IL-1) have a pro-inflammatory effect in all targets of the body. However, every inflammatory disease is characterized by a peculiar profile of secretion of cytokines. TNF alpha blocking agents are a major advance in the treatment of of rheumatoid arthritis, spondylarthropathies and Crohn disease. To date, the most common adverse events are reactions to infusions and reactivation of active tuberculosis with infliximab. Association of another immunosuppressive drug, such as methotrexate, decreases the first of these adverse events. IL1-RA is an inhibitor of IL-1 effects which have demonstrated its efficiency in rheumatoid arthritis. These anticytokines represent a dramatic progress in the treatment of inflammatory diseases but we have to stay very careful concerning the possible increased risk of infection or cancer.

Mariette X. · Rheumatology Department, Bicêtre Teaching Hospital, Le Kremlin Bicêtre, Paris XI University, France. · Joint Bone Spine. · Pubmed #12184431 No free full text.

Abstract: A precise definition of primary Sjögren's syndrome resting on 'revised' or 'international' criteria has been accepted by most experts. This is important because the symptoms of primary Sjögren's syndrome, namely, dryness, fatigue, and pain, are common in the population at large and can occur in the absence of autoimmune disease as a result of medication use, anxiety and depression, or normal aging. This widely accepted definition is particularly valuable as a tool for obtaining homogenous patient populations for trials of new therapeutic agents. In this review article, before discussing treatments for complications and current hopes about second-line drugs, we present an update on available treatments forthe symptomatic triad (dryness, fatigue, and diffuse pain) seen in autoimmune Sjögren's syndrome and in some cases of isolated sicca syndrome. These very bothersome and permanent symptoms have a negative effect on quality of life. The most recent data show that systemic cholinergic agonists (pilocarpine and cevimiline) are effective in the symptomatic treatment of dryness, that cyclosporine eye drops may relieve ocular symptoms, and that TNFalpha inhibitors may find a new indication in Sjögren's syndrome.

Mariette X. · Department of Rheumatology, Hôpital de Bicêtre, Université Paris Sud, Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #11602464 links to  free full text

Abstract: BACKGROUND: The occurrence of B cell non-Hodgkin's lymphoma is a complication of Sjögren's syndrome (SS) and, at least in some countries, of chronic hepatitis C virus (HCV) infection. Lymphomas occurring in both diseases share a number of characteristics: predominance of low grade, marginal zone histological type, frequency of mucosal localisation, possible transformation into a large B cell lymphoma, association with asymptomatic low level cryoglobulinaemia, absence of virus within lymphoma cells, but localisation of lymphomas in organs where the chronic viral infection is active in patients with HCV and where the autoimmune disease is active in patients with SS. HYPOTHESIS: It is proposed that in both diseases the first event of lymphomagenesis is the chronic stimulation at the site of the disease of polyclonal B cells secreting rheumatoid factor (RF). Then, that these RF B cells may become monoclonal and disseminate in other organs. The monoclonal secreted RF complexed with polyclonal IgG may cryoprecipitate. The following step would be a chromosomal abnormality (for example, trisomy 3 or bcl-2 translocation) which would confer to these cells a low grade B cell lymphoma comportment. A last event (for example, a mutation of p53) might transform this low grade B cell lymphoma into a high grade, large B cell lymphoma. The non-random utilisation of VH and VL by SS associated lymphoma B cells and the recent demonstration that these lymphoma B cells may display RF activity support the hypothesis that these lymphomas grow through an autoantigen driven process. CONCLUSION: The best preventive treatment of lymphoproliferations occurring in SS probably consists in decreasing the hyperactivation of autoreactive B cells when it is present, allowing the use of immunosuppressive drugs such as methotrexate or even tumour necrosis factor alpha antagonists, which in theory could favour other types of lymphoproliferation.

Youinou P, Mariette X. · Laboratoire d'immunologie, Institut de synergie des sciences et de la santé CHU BP 824 29609 Brest. · Rev Prat. · Pubmed #11252942 No free full text.

Abstract: Sjögren's syndrome presents as an autoimmune exocrinopathy, and the term autoimmune epitheliitis has recently been coined. The major lesion is a lymphocyte infiltrate affecting the salivary glands and consisting predominantly of activated CD4+ T cells. The remaining 20% B lymphocytes, first polyclonal, turn out to be monoclonal. Epithelial cells are endowed with a key-part in the play, inasmuch as they gather together most of the Sjögren's syndrome-specific target autoantigens within apoptotic bodies, and possess all the characteristics of antigen presenting cells. There appears to be every likelihood that the sequence is triggered off by a thus far unknown virus.

Mariette X. · Service d'Immuno-Hématologie Hôpital Saint-Louis, Paris, France. · Leuk Lymphoma. · Pubmed #10194125 No free full text.

Abstract: The occurrence of non Hodgkin's lymphoma (NHL) is the most serious complication of Sjögren's syndrome (SS). Taking the opportunity to study 16 patients with lymphoma and an underlying SS, we performed a review of literature concerning SS and lymphoma and made an hypothesis on the physiopathology of lymphoproliferation in patients with SS. Lymphomas occurring in patients with SS are in most cases low grade marginal zone lymphomas (MZL). They arise frequently in mucosal extranodal sites, not only in the salivary glands but also the stomach and the lung. These lymphomas are not associated with viruses including hepatitis C virus (HCV), Epstein-Barr virus, human herpes virus 8 or human T lymphotropic virus-I, known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or anti-oncogenes described in other lymphomas are also detected in SS-associated lymphomas. Lymphomas complicating SS share a number of characteristics with lymphomas complicating HCV infection. We make the assumption that, in both diseases, the first event of lymphomagenesis is the chronic stimulation, on the site of the disease, of polyclonal B-cells secreting rheumatoid factor (RF). Then, these RF B-cells may become monoclonal and disseminate in other organs. The monoclonal secreted RF complexed with polyclonal IgG may cryoprecipitate. The following step would be a chromosomal abnormality (e.g. trisomy 3) which would confer to these cells a low grade B-cell lymphoma compartment. A last event (e.g. mutation of p53) could transform this low grade B-cell lymphoma into a high grade large B-cell lymphoma. If this hypothesis was correct, most of B-cell lymphomas associated with SS should have a surface immunoglobulin with RF activity and should grow through an auto-antigen driven process.

Vauloup C, Krzysiek R, Greangeot-Keros L, Wendling D, Goupille P, Brault R, Brousse C, Mariette X, Emilie D. · Service de Microbiologie-Immunologie Biologique, hôpital A. Béclère, Assistance Publique-Hôpitaux de Paris. · Eur Cytokine Netw. · Pubmed #17353164 No free full text.

Abstract: BACKGROUND: Chronic hepatitis C infection is frequently associated with a mixed cryoglobulinaemia and circulating auto-antibodies, especially anti-smooth muscle cells (SMA) and anti-liver/kidney/microsome type 1 (LKM-1) anti-tissue antibodies. Treatments with TNF antagonists favour the emergence of auto-antibodies, and particularly anti-dsDNA antibodies. OBJECTIVE: To determine the impact of TNF antagonists on hepatitis C-related immune abnormalities. METHODS: We prospectively monitored for 14 weeks, six patients with actively replicating chronic hepatitis C, initiating an anti-TNF treatment for an associated rheumatoid arthritis. RESULTS: Anti-nuclear and anti-dsDNA antibodies were induced in two and three patients, respectively. Treatment had no impact on the production of antibodies against extractable nuclear antigens, and it did not induce anti-tissues antibodies in any patient. Cryoglobulinaemia appeared in 2/6 patients, and it persisted in 2 others. No patient developed any news signs of autoimmunity. HCV viraemia remained unchanged. CONCLUSIONS: Induction of auto-antibodies by TNF antagonist treatments does not involve anti-tissues antibodies, even in patients with actively replicating chronic hepatitis C prone to produce anti-SMA and anti-LKM-1 antibodies. In contrast, TNF antagonists may favour emergence of cryoglobulinaemia in such patients.

Burmester GR, Mariette X, Montecucco C, Monteagudo-Sáez I, Malaise M, Tzioufas AG, Bijlsma JW, Unnebrink K, Kary S, Kupper H. · Department of Rheumatology and Clinical Immunology, Charité-University Medicine Berlin, Charitéplatz 1, 10117 Berlin, Germany. · Ann Rheum Dis. · Pubmed #17329305 links to  free full text

Abstract: OBJECTIVE: To evaluate the safety and effectiveness of adalimumab alone or in combination with standard disease-modifying antirheumatic drugs (DMARDs) for the treatment of rheumatoid arthritis (RA). METHODS: Patients with active RA despite treatment with DMARDs or prior treatment with a tumour necrosis factor antagonist participated in a multicentre, open-label clinical study of adalimumab 40 mg every other week for 12 weeks with an optional extension phase. Patients were allowed to continue with pre-existing traditional DMARDs. Long-term safety results are reported for all patients (4210 patient-years (PYs) of adalimumab exposure). The observed effectiveness results at week 12 are reported using American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria. RESULTS: Among the 6610 treated patients, adalimumab was generally well tolerated. Serious infections occurred in 3.1% of patients (5.5/100 PYs, including active tuberculosis, 0.5/100 PYs). Demyelinating disease (0.06%) and systemic lupus erythematosus (0.03%) were rare serious adverse events. The standardised incidence ratio of malignancy was 0.71 (95% CI 0.49 to 1.01). The standardised mortality ratio was 1.07 (95% CI 0.75 to 1.49). At week 12, 69% of patients achieved an ACR20 response, 83% a moderate, and 33% a good EULAR response. Adalimumab was effective in combination with a variety of DMARDs. The addition of adalimumab to antimalarials was comparably effective to the combination of adalimumab and methotrexate. CONCLUSIONS: Considering the limitations of an open-label study, adalimumab alone or in combination with standard DMARDs appeared to be well tolerated and effective in 6610 difficult-to-treat patients with active RA treated in clinical practice.

Mariette X, Ravaud P, Steinfeld S, Baron G, Goetz J, Hachulla E, Combe B, Puéchal X, Pennec Y, Sauvezie B, Perdriger A, Hayem G, Janin A, Sibilia J. · Service de Rhumatologie, Hôpital de Bicêtre AP-HP, and Université Paris-Sud, Le Kremlin Bicêtre, France. · Arthritis Rheum. · Pubmed #15077311 links to  free full text

Abstract: OBJECTIVE: There is no effective treatment for patients with primary Sjögren's syndrome (SS). Since tumor necrosis factor alpha (TNF alpha) could be a key element in the pathogenesis of primary SS, we conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate the effect of infliximab in primary SS. METHODS: A total of 103 patients with primary SS were randomly assigned to receive infliximab infusions (5 mg/kg) or placebo at weeks 0, 2, and 6 and were followed up for 22 weeks. All patients fulfilled the new American-European Consensus Group criteria for SS and had active disease as assessed by values >50 mm on 2 of 3 visual analog scales (VAS) (0-100 mm) that evaluated joint pain, fatigue, and buccal, ocular, skin, vaginal, or bronchial dryness. A favorable overall response was defined as the patient having > or =30% improvement between weeks 0 and 10 in the values on 2 of the 3 VAS. Secondary end points were values on each VAS separately, the number of tender and swollen joints, the basal salivary flow rate, results of the Schirmer test for lacrimal gland function, the focus score on labial salivary gland biopsy, the level of C-reactive protein, and the erythrocyte sedimentation rate evaluated at weeks 0, 10, and 22, as well as quality of life evaluated by use of the generic Short Form 36 questionnaire administered at weeks 0, 10, and 22. RESULTS: At week 10, 26.5% of patients receiving placebo and 27.8% of patients treated with infliximab had a favorable overall response (P = 0.89), and at week 22, 20.4% of the placebo group and 16.7% of the infliximab group had a favorable response (P = 0.62). In addition, the 2 groups did not differ in any of the secondary end points over the 22 weeks of the trial. Severe adverse events reported in the infliximab group did not differ from those observed in previous studies. CONCLUSION: This randomized, double-blind, placebo-controlled study of an anti-TNF agent did not show any evidence of efficacy of infliximab in primary SS.

Labetoulle M, Mariette X, Joyeau L, Baudouin C, Kirsch O, Offret H, Frau E. · Service d'Ophtalmologie, Hospital de Bicetre, Assistance Publique-Hopitaux de Paris, 94275 Le Kremlin-Bicetre, Cedex, France. · J Fr Ophtalmol. · Pubmed #12399722 links to  free full text

Abstract: PURPOSE: To determine the cut-off value of the phenol red-impregnated thread test (Zone-Quick((R)), Menicon trade mark ) for the diagnosis of ocular sicca syndrome using the ROC (receiver operating characteristic) procedure and to estimate the agreement with the Schirmer I test (without anesthetics). MATERIAL: and methods: Fifty-four consecutive patients (including 50 females) with dry eyes, presumably related to an immune disorder, were recruited on the basis of subjective ocular symptoms and medical history (sicca syndrome). Both the phenol red thread (PRT) test and the Schirmer I test (testing periods, 15s and 5min, respectively) were performed in both eyes in random order. Only the lowest result for each test was used in statistical analyses. The same procedure was applied to 29 normal volunteers (no subjective symptoms). The patient and the control groups were matched for age and gender (mean age, 58.1 and 59.6, respectively). RESULTS: The ROC procedure showed that a cut-off value of 12mm in the PRT test provided the best ratio between sensitivity and specificity (56% and 69%, respectively) for the detection of dry eyes. Using this threshold, the agreement with the Schirmer I test was highly significant (kappa test; P<10(-3)). However, discordant results were observed in 32% of subjects. CONCLUSION: Giving a cut-off value at 12mm, the sensitivity and specificity of the PRT are 56% and 69%, respectively. Even if the agreement with the Schirmer I test is highly significant, 32% of patients have discordant results. These two methods of functional assessment of tear secretion are therefore complementary and further studies remain necessary to better understand the place of both tests in clinical practice.

Tubach F, Salmon D, Ravaud P, Allanore Y, Goupille P, Bréban M, Pallot-Prades B, Pouplin S, Sacchi A, Chichemanian RM, Bretagne S, Emilie D, Lemann M, Lorthololary O, Mariette X, Anonymous00120. · Université Paris 7 Denis Diderot; INSERM U738; Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bichat, Biostatistique et Recherche Clinique, Paris, France. · Arthritis Rheum. · Pubmed #19565495 No free full text.

Abstract: OBJECTIVE: Tuberculosis (TB) is associated with anti-tumor necrosis factor (anti-TNF) monoclonal antibody (mAb) therapy, but whether this association is drug-specific remains a concern. Our objective was to describe cases of TB associated with anti-TNF mAb therapy, identify risk factors, and estimate the incidence. METHODS: We conducted an incidence study and a case-control analysis to investigate the risk of newly diagnosed TB associated with the use of anti-TNF agents. As part of the French Research Axed on Tolerance of Biotherapies (RATIO) registry, for 3 years we collected cases of TB among French patients receiving anti-TNF mAb therapy for any indication; for each case, 2 patients treated with anti-TNF agents served as control subjects. RESULTS: We collected 69 cases of TB in patients treated for rheumatoid arthritis (n = 40), spondylarthritides (n = 18), inflammatory colitis (n = 9), psoriasis (n = 1) and Behçet's disease (n = 1) with infliximab (n = 36), adalimumab (n = 28), and etanercept (n = 5). None of the patients had received correct chemoprophylactic treatment. The sex- and age-adjusted incidence rate of TB was 116.7 per 100,000 patient-years. The standardized incidence ratio (SIR) was 12.2 (95% confidence interval [95% CI] 9.7-15.5) and was higher for therapy with infliximab and adalimumab than for therapy with etanercept (SIR 18.6 [95% CI 13.4-25.8] and SIR 29.3 [95% CI 20.3-42.4] versus SIR 1.8 [95% CI 0.7-4.3], respectively). In the case-control analysis, exposure to infliximab or adalimumab versus etanercept was an independent risk factor for TB (odds ratio [OR] 13.3 [95% CI 2.6-69.0] and OR 17.1 [95% CI 3.6-80.6], respectively). Other risk factors were age, the first year of anti-TNF mAb treatment, and being born in an endemic area. CONCLUSION: The risk of TB is higher for patients receiving anti-TNF mAb therapy than for those receiving soluble TNF receptor therapy. The increased risk with early anti-TNF treatment and the absence of correct chemoprophylactic treatment favor the reactivation of latent TB.

Pham T, Claudepierre P, Constantin A, Fautrel B, Gossec L, Gottenberg JE, Goupille P, Hachulla E, Masson C, Morel J, Saraux A, Schaeverbeke T, Wendling D, Mariette X, Sibilia J. · Service de Rhumatologie, CHU Conception, Marseille, France. · Joint Bone Spine. · Pubmed #19560051 No free full text.

Abstract: OBJECTIVES: To elaborate a how-to-use abatacept material intended to help physicians in the management of patients with inflammatory diseases treated with this drug in routine practice. METHODS: 1) Selection of the relevant domains by a rheumatologists' panel; 2) Search for published evidence in each domain; 3) Elaboration of the clinical tool guide with a 3-level gradation of evidence (evidence-based medicine EBM, official recommendations and expert's opinion). The experts were 11 academic rheumatologists with a large experience in prescribing abatacept and in managing rheumatoid arthritis. They were all members of the CRI (Club Rhumatismes et Inflammation), a section of the French Rheumatology Society dedicated to the inflammatory rheumatic diseases. Each fact sheet was reviewed by two other experts; 4) Regular updating based on medical literature and postmarketing surveillance data. RESULTS: Four domains were considered relevant: abatacept contraindications, management of side effects or associated diseases appearing during abatacept treatment, management of "practical situations" such as surgery or pregnancy, physician and patient information. After the literature analysis and discussion during an experts' meeting, a consensus was reached on: a pre-treatment checklist aimed at searching abatacept contraindications; a what-to-do document when facing side effects or associated diseases (autoimmune pathology, bacterial or viral infections, cardiovascular diseases, intolerance to abatacept, solid or haematological malignancy) or "practical situations" (surgery, pregnancy, vaccination, travel, drug-drug interactions); an example of standard information letter to be addressed to the attending physician (rheumatologist and general practitioner); an example of standard information letter to be addressed to the patient. CONCLUSION: Based on both an EBM approach and an expert's opinion approach, this abatacept clinical tool guide should provide assistance to all physicians attending patients treated with abatacept. For a better implementation in clinical practice, this tool guide will be available online at www.cri-net.com and regularly updated.

Tebib J, Mariette X, Bourgeois P, Flipo RM, Gaudin P, Le Loët X, Gineste P, Guy L, Mansfield CD, Moussy A, Dubreuil P, Hermine O, Sibilia J. · Service de Rhumatologie, Centre Hospitalier Lyon-Sud, 765 chemin du Grand-Revoyet, 69495 Pierre-Bénite, France. · Arthritis Res Ther. · Pubmed #19549290 links to  free full text

Abstract: INTRODUCTION: Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA. METHODS: This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12. RESULTS: Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends. CONCLUSIONS : Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation. TRIAL REGISTRATION: ClinicalTrials.gov NCT00831922.

Miceli-Richard C, Gestermann N, Amiel C, Sellam J, Ittah M, Pavy S, Urrutia A, Girauld I, Carcelain G, Venet A, Mariette X. · Rhumatologie, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, 94275 Le Kremlin Bicêtre, France. · Arthritis Res Ther. · Pubmed #19470150 links to  free full text

Abstract: INTRODUCTION: There is a suspicion of increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferations in patients with inflammatory arthritides receiving immunosuppressive drugs. We investigated the EBV load and EBV-specific T-cell response in patients treated with methotrexate (MTX) or anti-TNF therapy. METHODS : Data for patients with rheumatoid arthritis (RA) (n = 58) or spondylarthropathy (SpA) (n = 28) were analyzed at baseline in comparison with controls (n = 22) and after 3 months of MTX or anti-TNF therapy for EBV load and EBV-specific IFNgamma-producing T cells in response to EBV latent-cycle and lytic-cycle peptides. RESULTS: The EBV load and the number of IFNgamma-producing T-cells after peptide stimulation were not significantly different between groups at baseline (P = 0.61 and P = 0.89, respectively). The EBV load was not significantly modified by treatment, for RA with MTX (P = 0.74) or anti-TNF therapy (P = 0.94) or for SpA with anti-TNF therapy (P = 1.00). The number of EBV-specific T cells was not significantly modified by treatment, for RA with MTX (P = 0.58) or anti-TNF drugs (P = 0.19) or for SpA with anti-TNF therapy (P = 0.39). For all patients, the EBV load and EBV-specific T cells were significantly correlated (P = 0.017; R = 0.21). For most patients, short-term exposure (3 months) to MTX or anti-TNF did not alter the EBV load or EBV-specific T-cell response but two patients had discordant evolution. CONCLUSIONS: These data are reassuring and suggest there is no short-term defect in EBV-immune surveillance in patients receiving MTX or anti-TNF drugs. However, in these patients, long term follow-up of EBV-specific T-cell response is necessary and the role of non-EBV-related mechanisms of lymphomagenesis is not excluded.