Rheumatoid Arthritis: Toussirot E

Wendling D, Toussirot E. · No affiliation provided · Rev Rhum Engl Ed. · Pubmed #10339773 No free full text.

This publication has no abstract.

Toussirot E, Streit G, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Bd. Fleming, F-25030 Besancon Cedex, France. · Recent Pat Inflamm Allergy Drug Discov. · Pubmed #19075965 No free full text.

Abstract: TNFalpha plays a pivotal role not only in the inflammatory process but also in the normal response against pathogens and therefore, interfering with this cytokine may increase the risk of infection. TNFalpha antagonists are commonly used in daily clinical practice for the treatment of inflammatory rheumatic diseases including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile idiopathic arthritis since the beginning of 2000. The spectrum of pathogens giving infectious disease in patients under anti-TNFalpha therapies ranges from common bacteria to more opportunistic organisms such as Mycobacterium tuberculosis. The infections which were described with TNFalpha inhibitors may have a benign course or may be a serious, life threatening disease, and may be localized or disseminated. These TNFalpha inhibitors related infections were described in the randomized clinical trials, and were then declared to post-marketing surveillance systems and special registries. Tuberculosis (TB) is the most frequent opportunistic infection which has been reported with TNFalpha antagonists and the highest risk appears to be associated with infliximab, and at a lesser extent with etanercept. Currently available data and recent patents on the risk of TB with adalimumab are not sufficient to conclude, but TB cases were also reported with this agent. The description of TB infections with TNFalpha inhibitors led to the establishment of new guidelines for screening patients at high risk of developing TB. These data highlight the importance of post-marketing surveillance and special registries for accurately evaluating the safety profile and particularly the infectious risk of this very effective class of drug in inflammatory rheumatic diseases.

Toussirot E, Roudier J. · Department of Rheumatology, University Hospital Jean Minjoz, Besançon; and EA 3186 Agents Pathogènes et Inflammation, University of Franche Comté, Besançon, France. · Best Pract Res Clin Rheumatol. · Pubmed #19028369 No free full text.

Abstract: Autoimmune diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren's syndrome (pSS) are complex disorders with a genetic background and the involvement of environmental factors, including viruses. The Epstein-Barr virus (EBV) is a plausible candidate for playing a role in the pathophysiology of these diseases. Both SLE and RA are characterized by high titers of anti-EBV antibodies and impaired T-cell responses to EBV antigens. Compared with normal subjects, elevated EBV load in peripheral blood has been observed in SLE and RA. EBV DNA or RNA has been evidenced in target organs of RA (synovium) or pSS (salivary glands). Finally, molecular mimicry has been demonstrated between EBV proteins and self antigens in these three conditions. In addition, SLE, RA, and pSS are associated with an increased risk of lymphoma with a potential role for EBV. The influence of new and emergent treatments of these autoimmune diseases (biological therapies) on EBV load and the course of latent EBV infection requires further studies.

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.

Toussirot E, Wendling D. · University Hospital Jean Minjoz, Department of Rheumatology, Besançon cedex, France. · Expert Opin Pharmacother. · Pubmed #17714062 No free full text.

Abstract: TNF-alpha has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis (RA). Drugs targeting TNF-alpha have been developed to neutralise the deleterious effects of this inflammatory cytokine. There are, at present, three drugs available for the treatment of RA patients with active disease who are refractory to conventional treatments including methotrexate: 2 monoclonal antibodies, infliximab and adalimumab, and a fusion protein with p75 receptors, etanercept. These three agents have proved to be effective and safe in large placebo-controlled trials enrolling patients with established or early disease and showed effectiveness in controlling signs and symptoms of the disease, improving quality of life and in slowing and even arresting the progression of radiographic damage. With the long-term surveillance of these drugs were described serious adverse events, particularly infections such as tuberculosis, especially with infliximab. The risk for malignancies under TNF-alpha antagonists, especially lymphoma, remains controversial. Specific recommendations are given by international experts for selecting and monitoring RA patients with TNF-alpha antagonists. Other drugs targeting TNF-alpha such as PEGylated molecules (CDP870 or certolizumab) are in development. These new biological therapies blocking TNF-alpha undoubtedly constitute a considerable advancement in the management of RA, but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary.

Toussirot E, Roudier J. · Rheumatology Department, Jean Minjoz Teaching Hospital, Boulevard A. Fleming, 25030 Besançon, France. · Joint Bone Spine. · Pubmed #17625943 No free full text.

Abstract: Numerous associations have been documented between the Epstein-Barr virus (EBV) and rheumatoid arthritis (RA). Thus, anti-EBV antibody titers are higher in RA patients than in healthy controls. Lymphocytes from RA patients show impaired responses to EBV. Several EBV antigens share similarities with self antigens; more specifically, the glycine/alanine repeats in EBNA-1 resemble synovial proteins and the EBV gp110 glycoprotein contains a copy of the shared epitope. Cell-mediated responses to EBV replicative cycle proteins and to gp110 have been documented in joint fluid from RA patients. In situ hybridization and PCR techniques have identified EBV antigens and genetic material within the rheumatoid synovium, albeit with variable yields. The EBV burden in peripheral blood mononuclear cells is higher in RA patients than in controls. EBNA-1 can undergo citrullination, and the EBV can induce antibodies to citrullinated peptides. RA patients are at increased risk for lymphoma, including EBV-associated lymphoma. Despite these multiple and complex links between EBV and RA, proof of a causal association is lacking. EBV infection may contribute indirectly to the pathophysiology of RA by impairing immune control of EBV replication, causing increased exposure to EBV antigens and, thereby, chronic inflammation. The effect of biotherapies for RA on EBV-host relations needs to be investigated.

Toussirot E, Streit G, Wendling D. · Department of Rheumatology, Jean Minjoz University Hospital, Bd Fleming, F-25030 Besançon Cedex, France. · Curr Med Chem. · Pubmed #17456023 No free full text.

Abstract: Adipokines are proteins produced by white adipose tissue, which is an active secretory organ. Regulation of immune and inflammatory responses is among the multiple physiological processes involving adipokines. Leptin, adiponectin and resistin are the most extensively studied adipokines. Leptin may promote inflammation by inducing Th1 phenotype development, whereas adiponectin may combat inflammation by reducing the production of pro-inflammatory cytokines. Resistin belongs to a family of proteins found in foci of inflammation, where they contribute to the inflammatory response. All three adipokines have been detected in synovial fluid from joints affected with the inflammatory disease rheumatoid arthritis (RA) or the degenerative disease osteoarthritis (OA). Recent evidence points to involvement of leptin in RA and OA and indicates that adiponectin and/or resistin mediate inflammation in arthritis. Thus, fat tissue is an active organ whose products contribute to inflammatory and degenerative processes underlying common joint diseases.

Michel F, Navellou JC, Ferraud D, Toussirot E, Wendling D. · Rheumatology Department, CHU Jean Minjoz Teaching Hospital, Boulevard Fleming, Besançon, cedex 25030, France. · Joint Bone Spine. · Pubmed #15681256 No free full text.

Abstract: DRESS (Drug Rash with Eosinophilia and Systemic Symptoms) is a drug-induced hypersensitivity syndrome that can mimic malignant lymphoma. We report a case in a 63-year-old woman who had been on sulfasalazine for 2 months to treat rheumatoid arthritis. She was admitted a few days after onset of a flu-like syndrome with a pruriginous maculopapular erythema initially involving the face, trunk, and proximal limbs; a fever of 41 degrees C; and enlargement of the liver, spleen, and several peripheral lymph nodes. Blood tests showed marked eosinophilia (9300/mm3), lymphocytosis, hyperbasophilic cells, and severe inflammation. DRESS syndrome was diagnosed. An indirect immunofluorescence assay for human herpesvirus 6 (HHV6) was positive, supporting recent HHV6 infection. Primary HHV6 infection and HHV6 reactivation have been incriminated in the genesis of DRESS syndrome. DRESS syndrome continues to carry a high mortality rate of about 10%. Drugs previously reported to cause DRESS syndrome include sulfasalazine, hydantoin, d-penicillamine, allopurinol, hydrochlorothiazide, and cyclosporine. A high index of suspicion for DRESS syndrome should be maintained in patients receiving these drugs. Serological tests for HHV6 should be performed routinely in patients with suspected DRESS syndrome, although uncertainty persists about the link between HHV6 infection and DRESS syndrome.

Toussirot E, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Cédex, France. · Expert Opin Pharmacother. · Pubmed #15013927 No free full text.

Abstract: TNF-alpha has been found to play a pivotal role in the pathogenic mechanisms of rheumatoid arthritis (RA). The overexpression of TNF-alpha in RA synovium, the data from in vitro synovial cell cultures with the use of anti-TNF-alpha antibody and the results from TNF-alpha blockade in animal models of arthritis argued for the importance of this cytokine in RA. Drugs targeting TNF-alpha have been developed to neutralise the deleterious effects of this inflammatory cytokine. There are currently three drugs available in the treatment of RA patients with active disease, which was refractory to conventional treatments including methotrexate, infliximab (a chimeric mouse/human monoclonal antibody), etanercept (a fusion protein combining 2 p75 TNF receptors with a Fc fragment of human IgG (1)) and adalimumab (a fully human monoclonal antibody). These three drugs have proved to be effective and safe in appropriate and well conducted clinical trials and showed effectiveness in slowing and even arresting the progression of radiographic damage. With the long-term surveillance of these drugs serious adverse events were described, particularly intracellular organism infections such as tuberculosis. Other drugs targeting TNF-alpha are in development and include monoclonal antibody (CDP571), pegylated molecules (CDP870 and PEG-r-Hu-sTNF-RI) or soluble p55 TNF receptor construct (lenercept). These new biological therapies blocking TNF-alpha undoubtedly constitute a considerable advance in the management of RA, but careful evaluation at the initiation of the treatment and long-term surveillance of the patients receiving such drugs remains necessary.

Lehuédé G, Toussirot E, Despaux J, Michel F, Wendling D. · Rheumatology department, CHU Jean-Minjoz, Besançon, France. · Joint Bone Spine. · Pubmed #12184439 No free full text.

Abstract: Yellow nail syndrome is characterized by ungual dystrophy, lower limb lymphedema, and pleural effusions or bronchiectasis. Rheumatoid arthritis is the autoimmune disorder most often associated with yellow nail syndrome. We report two new cases of yellow nail syndrome in patents receiving thiol compound therapy for rheumatoid arthritis. Eight similar cases have been reported since 1979, suggesting a possible causative effect of this class of drugs.

Lohse A, Despaux J, Auge B, Toussirot E, Wendling D. · Rheumatology Department, Jean Minjoz Teaching Hospital, Besançon, France. · Rev Rhum Engl Ed. · Pubmed #10418064 No free full text.

Abstract: Rheumatoid arthritis is the most commonly reported host-related risk factor for septic arthritis. This risk is highest in severe, seropositive, long-standing (mean, 10 years) rheumatoid arthritis responsible for extraarticular symptoms and treated with systemic glucocorticoids. The clinical presentation of the joint infection is often atypical, leading to diagnostic wanderings. In 25% of cases, the infection is polyarticular, with 3.5 involved joints on average. Staphylococcus aureus is the most common causative organism. Streptococcus pneumoniae causes 5% of all cases of septic arthritis and is more often responsible for polyarticular infections than other organisms. Polyarticular septic arthritis carries a poor prognosis, with a mortality rate of 50% in rheumatoid arthritis patients. Despite its low incidence, polyarticular septic arthritis should be routinely considered in the differential diagnosis of rheumatoid flares. We report a case of pneumococcal septic arthritis involving five joints in a patient with known rheumatoid arthritis. Three other cases with involvement of more than four joints have been published.

Charpin C, Balandraud N, Guis S, Roudier C, Toussirot E, Rak J, Lambert N, Martin M, Reviron D, Roudier J, Auger I. · INSERM UMR 639, Université de la Méditerranée and Rheumatology, APHM, Marseille, France. · Clin Exp Rheumatol. · Pubmed #18799094 No free full text.

Abstract: OBJECTIVE: To test whether the presence of RA associated HLA-DRB1*0101, HLA-DRB1*0401 and HLA-DRB1*0404 alleles individually influences anti-cyclic citrullinated peptide antibodies (anti-CCP) production. METHODS: The frequency of anti-CCP antibodies was calculated in the sera of 260 RA patients expressing either two (double dose genotypes SE+/SE+), one (single dose genotypes SE+/SE-) or no RA associated HLA-DR alleles (SE-/SE-). Anti-CCP antibodies titers were also determined. RESULTS: RA associated HLA-DR alleles are not mandatory for production of anti-CCP. We found that 68% of SE-/SE- patients were anti-CCP positive. There was no significant difference in anti-CCP between SE negative patient (SE-/SE-) and patients expressing at least one SE (SE+/SE+ and SE+/SE-) (p=0.140). We observed no statistical difference in anti-CCP between RA patients expressing one or two SE (82% vs. 77%, p=0.577). Among SE+/SE-patients, HLA-DRB1*0404 was associated with anti-CCP with a statistically significant difference compared with SE negative patients (90% anti-CCP positive, p=0.02). HLA-DRB1*0404 was also associated with high titers of anti CCP with a statistically significant difference compared with HLA-DRB1*0401 and HLA-DRB1*0101 patients (p=0.025). CONCLUSIONS: The RA-associated HLA-DRB1*0404 allele was the most strongly associated with the presence of anti-CCP in RA sera. Moreover, HLA-DRB1*0404 patients had higher titers of anti CCP than patients with other RA associated HLA-DR alleles.

Wendling D, Streit G, Toussirot E, Prati C. · Service de Rhumatologie, CHU Minjoz et Université de Franche-Comté, 25030 Besançon, France. · Joint Bone Spine. · Pubmed #18674945 No free full text.

Abstract: OBJECTIVE: To assess the rate of occurrence and outcomes of herpes zoster in patients taking TNFalpha antagonists. METHODS: Retrospective review of the medical records of 300 patients who received TNFalpha antagonists to treat chronic inflammatory joint disease. RESULTS: We identified 9 (9/300, 3%) patients who experienced herpes zoster, 6 women and 3 men, with rheumatoid arthritis (n=7) or ankylosing spondylitis (n=2). The drug was infliximab in 4 patients, adalimumab in 2 patients, and etanercept in 3 patients, including 2 patients with a prior history of infliximab therapy (for 12 and 36 months, respectively). Mean treatment duration at the occurrence of herpes zoster was 27 months (range, 6-42 months). DISCUSSION: Glucocorticoid therapy (n=7) and methotrexate therapy (n=6) were the only risk factors identified in our study. Mean follow-up was 26 months. All 9 patients achieved a full recovery with antiviral treatment and interruption of the TNFalpha antagonist. One patient experienced a recurrence after resuming TNFalpha antagonist therapy. CONCLUSION: The scant data in the literature suggest a higher risk of herpes zoster with anti-TNFalpha antibodies than with the soluble receptor. The role for concomitant treatments (glucocorticoids and methotrexate) should be taken into account.

Guis S, Balandraud N, Bouvenot J, Auger I, Toussirot E, Wendling D, Mattei JP, Nogueira L, Mugnier B, Legeron P, Landt O, Serre G, Roudier J, Roudier C. · INSERM UMR 639 and Assistance Publique Hôpitaux de Paris, Hôpital de la Conception, Marseille, France. · Arthritis Rheum. · Pubmed #18050183 links to  free full text

Abstract: OBJECTIVE: To determine whether the -308 A/G tumor necrosis factor alpha (TNFalpha) gene polymorphism can predict the outcome of etanercept therapy in 86 patients with rheumatoid arthritis (RA), as already observed in patients treated with infliximab. METHODS: Eighty-six RA patients treated with etanercept were genotyped for -308 A/G TNFalpha gene polymorphism by polymerase chain reaction and melting curve analysis, using specific gene primers and probes. Patients were subdivided into group A (G/A genotype) and group G (G/G genotype). We compared clinical responses to etanercept between groups A and G after 6 months, using the Disease Activity Score in 28 joints (DAS28). After 12-month treatment, 48 of 86 patients were evaluated again. RESULTS: Of 86 patients, 18 (21%) belonged in group A and 68 (79%) belonged in group G. After 6-month treatment, 55.6% of patients in group A and 82.4% of patients in group G had DAS28 improvement >1.2 (P = 0.027 by chi-square). The mean +/- SD DAS28 improvement was 1.69 +/- 1.31 in group A and 2.23 +/- 1.19 in group G (P = 0.098 by t-test). After 1-year treatment 48 patients were tested again: 10 (21%) belonged in group A and 38 (79%) belonged in group G. Forty percent of patients in group A and 87% in group G had DAS28 improvement >1.2 (P = 0.005 by chi-square). The mean +/- SD DAS28 improvement was 1.334 +/- 1.37 in group A and 2.29 +/- 1.47 in group G (Mann-Whitney U test = 115, P = 0.0057). CONCLUSION: RA patients with a -308 G/G TNFalpha genotype respond to etanercept better than patients with a -308 A/G genotype.

Morel J, Deschamps V, Toussirot E, Pertuiset E, Sordet C, Kieffer P, Berthelot JM, Champagne H, Mariette X, Combe B. · Department of Immuno-Rheumatology, Montpellier I University and Lapeyronie Teaching Hospital, 34295 Montpellier, Cedex 5 France. · Ann Rheum Dis. · Pubmed #17604284 No free full text.

Abstract: OBJECTIVE: To date, only a few series of patients with paraneoplastic arthritis have been published. The charts of patients with cancer-associated arthritis were collected in order to describe characteristics of this rheumatism. METHODS: A questionnaire was created for this study and validated by experts based on specific criteria of inclusion and exclusion. Histology of neoplasia was included. RESULTS: In all, 16 males and 10 females with a mean (range) age of 57.5 years (28-85) were recruited from 17 nationwide centres in France. Patients presented with symmetric polyarthritis involving wrists and hands (85%) and extra-articular symptoms were frequent (84%). There was no specific biologic or radiographic feature. The mean (range) delay between the diagnosis of rheumatism and neoplasia was 3.6 months (0-21.2). Tumours were usually diagnosed after articular symptoms occurred (88.5%). Twenty patients had a solid cancer, and six a haematological malignancy. Adenocarcinoma of the lungs was the most frequent type of solid cancer (60%). Tumours were diagnosed at an early stage, which may explain the good median survival of 1.21 years (range 0.64-present) with a mean follow-up of 1.9 years (range 0.16-10). The percentage of articular symptoms resolution was significantly higher in patients with solid tumours, as compared to patients with haemopathy (p = 0.007). In cases of tumour relapse, rheumatic symptoms did not recur for 75% of patients. CONCLUSIONS: Underlying neoplasia should be considered in male patients with new onset polyarthritis, smokers, and particularly in patients chronically ill. Additional investigations should then be performed to diagnose cancer at an early stage.

Toussirot E, Robinet E, Saas P, Chabod J, Augé B, Cozma G, Tiberghien P, Roudier J, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Bd Fleming, F-25030 Besançon cédex, France. · Autoimmunity. · Pubmed #16891218 No free full text.

Abstract: The Escherichia Coli bacterial extract (OM-89) is used in the treatment of rheumatoid arthritis (RA). We evaluated the immunological changes induced by oral administration of OM-89 in 12 RA patients (polyclonal T cell reactivity to PHA, T cell precursor frequencies specific for OM-89 and Tetanus toxoid (TT), a control antigen and the release of Th1 (IFN-gamma, TNF-alpha), Th2 (IL-4) and T regulatory 1 cell (Tr1) (IL-10) cytokines in the supernatants of PBMC cultures. Stimulation index in response to PHA decreased at month 3 as well as T cell precursor frequencies specific for TT with similar trends for OM-89-specific T cell precursor frequencies. OM-89 induced a strong production of IL-10, a significant decrease in IL-4 production while TNF-alpha and IFN-gamma production tended to decrease during the study.Our results suggest that OM-89 has immunomodulatory properties by inducing changes in PBMC cytokines release suggestive of an induced Tr1 response to OM-89.

Wendling D, Balblanc JC, Brousse A, Lohse A, Lehuede G, Garbuio P, Toussirot E, Auge B, Jacques D. · No affiliation provided · Ann Rheum Dis. · Pubmed #16100348 links to  free full text

This publication has no abstract.

Wendling D, Materne GE, Michel F, Lohse A, Lehuede G, Toussirot E, Massol J, Woronoff-Lemsi MC. · Rheumatology Department, Minjoz Teaching Hospital, CHU Minjoz, 25030 Besançon, France. · Joint Bone Spine. · Pubmed #16038842 No free full text.

Abstract: Infliximab is a major breakthrough in the management of rheumatoid arthritis (RA). We evaluated infliximab continuation rates and reasons for discontinuation in patients with RA. PATIENTS AND METHODS: We studied patients with RA started on infliximab at any time between March 2000 and December 2002, under the conditions of everyday practice (as opposed to clinical trial settings), as recommended by the French marketing license (3 mg/kg as an intravenous infusion at weeks 0, 2, and 6 then at 8-week intervals). The number of infliximab infusions, side effects, and nonresponse rates was recorded. The Kaplan-Meier method was used to evaluate treatment continuation. Reasons for discontinuation were studied. RESULTS: We included 41 patients, with a mean age of 54 years, a mean RA duration of 9 years, and a mean of three previous disease-modifying antirheumatic drug treatments. The total number of infliximab infusions was 461 with a mean of 10.8 per patient and a mean follow-up under treatment of 15.3 months. The proportions of patients still on infliximab were 82%, 74%, and 67% after 6, 12, and 24 months, respectively. The main reasons for discontinuation were escape phenomenon (n = 6, 42.8% of discontinuations) and allergy (n = 3); in one case each, the reason was primary ineffectiveness, severe infection, plans to start a pregnancy, poor compliance, and unavailability for follow-up. There were 59 recorded episodes of side effects, with a profile similar to that in the literature and in postmarketing databases. CONCLUSION: The infliximab continuation rate in everyday practice in patients with RA (67% after 2 years) was consistent with published data and with the results of controlled trials.

Ramos-Casals M, Loustaud-Ratti V, De Vita S, Zeher M, Bosch JA, Toussirot E, Medina F, Rosas J, Anaya JM, Font J, Anonymous00012. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, Barcelona, Spain. · Medicine (Baltimore). · Pubmed #15758837 No free full text.

Abstract: To define the clinical and immunologic pattern of expression of Sjögren syndrome (SS) associated with chronic hepatitis C virus (HCV) infection, we conducted a multicenter study aiming to collect a large number of patients with SS and HCV infection. Inclusion criteria were the fulfillment of at least 4 of the classification criteria for SS proposed by the European Community Study Group and repeated positive HCV serology, confirmed by recombinant immunoblot assay and/or detection of serum HCV-RNA by polymerase chain reaction. One hundred thirty-seven patients were included (104 female and 33 male; mean age, 65 yr). Seventy-nine (58%) patients presented a systemic process with diverse extraglandular manifestations, with articular involvement (44%), vasculitis (20%), and neuropathy (16%) being the most frequent features observed. The main immunologic features were antinuclear antibodies (65%), hypocomplementemia (51%), and cryoglobulinemia (50%). Cryoglobulins were associated with a higher frequency of cutaneous vasculitis, rheumatoid factor, and hypocomplementemia. Thirty-two (23%) patients had positive anti-Ro/SS-A and/or anti-La/SS-B antibodies; these patients were predominantly women and had a higher prevalence of some extraglandular features and a lower frequency of liver involvement. Nineteen (14%) patients developed neoplasia, with hematologic neoplasia (8 cases) and hepatocellular carcinoma (6 cases) being the most frequent types. Eighty-five percent of SS-HCV patients also fulfilled the recently proposed 2002 classification criteria for SS.In conclusion, HCV-associated SS is indistinguishable in most cases from the primary form using the most recent set of classification criteria. Chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because the virus may be implicated in the development of SS in a specific subset of patients. We propose the term "SS secondary to HCV" when these patients fulfill the 2002 classification criteria for SS.

Toussirot E, Nguyen NU, Dumoulin G, Aubin F, Cédoz JP, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Bd Fleming, 25030 Besançon cedex, France. · Rheumatology (Oxford). · Pubmed #15466894 links to  free full text

Abstract: OBJECTIVES: Hormonal factors playing a role in bone mass and body composition have been rarely assessed in rheumatoid arthritis (RA). In this study, we aimed to evaluate the growth hormone (GH)-insulin-like growth factor-I (IGF-I)-insulin-like growth factor binding protein-3 (IGFPB-3) axis and serum leptin levels in patients with RA and to determine whether these hormonal/growth factors may influence bone mass and body composition in RA. METHODS: Serum GH, IGF-I, IGFPB-3 and leptin were evaluated in 38 corticosteroid-treated RA patients, 14 non-RA patients under corticosteroids (corticosteroid controls, CC) and 32 healthy controls (HC). Bone density was evaluated using dual X-ray absorptiometry (DEXA), and expressed as bone mineral density (BMD), and quantitative ultrasound (QUS). Body composition was assessed by DEXA. RESULTS: The three groups differed regarding femoral neck, total body BMD, lean mass and QUS parameters with lower values in the RA group (all P < or = 0.05). Growth hormone was higher in RA patients (P=0.0001) while IGF-I and IGFBP-3 did not differ between the three groups. In RA patients there was a tendency to high serum leptin levels and leptin strongly correlated with fat mass (r=0.83, P<0.0001), but not with bone mass measurements or inflammatory parameters. There were no differences for lean mass, GH and leptin between CC and HC. CONCLUSION: Our results suggest that these GH and leptin modifications could have an influence on both bone mass and body composition in RA.

Drouart M, Saas P, Billot M, Cedoz JP, Tiberghien P, Wendling D, Toussirot E. · Department of Rheumatology, University Hospital Jean Minjoz, Besançon, France. · Clin Exp Immunol. · Pubmed #12653851 links to  free full text

Abstract: Angiogenesis is involved in chronic inflammatory joint diseases such as rheumatoid arthritis (RA). Vascular endothelial growth factor (VEGF) plays a crucial role in angiogenesis. The spondylarthropathies (SpA) are characterized by enthesitis and synovitis, in which blood vessels participate. The objective of this study was to investigate serum VEGF levels and their potential associations with disease activity markers for SpA. Sera were collected from 105 patients with SpA (72 with ankylosing spondylitis (AS), four with psoriatic arthritis (PsA), six with reactive arthritis (ReA), eight with enteropathic arthropathy and 15 with undifferentiated SpA), 50 patients with rheumatoid arthritis (RA) and 64 healthy controls. Disease activity in SpA patients was assessed using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and laboratory parameters of inflammation [erythrocyte sedimentation rate (ESR) and C-reactive protein level (CRP)]. Serum VEGF levels were significantly higher in SpA patients (316.4 +/- 215.6 pg/ml) and RA patients (405.2 +/- 366.5) than in controls (217.3 +/- 145.2) (P = 0.003). In SpA patients, serum VEGF levels correlated with disease activity indices (BASDAI: r = 0.22, P = 0.04; ESR: r = 0.3, P = 0.003; and CRP: r = 0.23, P = 0.02). Serum VEGF levels were not associated with presence of extra-articular manifestations or syndesmophytes or with the grade of sacroiliitis. These results suggest that VEGF and therefore angiogenesis may play a role in SpA pathogenesis and may serve as a disease activity marker in SpAs.

Lohse A, Carbillet JP, Onimus M, Stevenel F, Toussirot E, Wendling D. · Rheumatology department, CHU Jean-Minjoz, 25030 Besançon cedex, France. · Joint Bone Spine. · Pubmed #12639622 No free full text.

Abstract: The term "intraosseous synovial cyst" is used to designate both the epiphyseal cyst-like lesions seen in patients with rheumatoid arthritis (RA) and mucoid cysts, which occur in a different setting. We report the case of a patient in whom a 4-cm cyst-like lesion developed in the left tibia 18 years after onset of RA and 6 years after osmic acid synovectomy of the left knee. Positive contrast arthrography and magnetic resonance imaging visualized a communication between the lesion and the joint space. Preexisting bone and joint lesions and increased intraarticular pressure play a major role in the genesis of cyst-like lesions in RA. In our patient, the osmic acid synovectomy may have contributed to the development of the lesion. "Synovial cyst" is a misnomer for these giant lesions, which are geodes rather than cysts. Despite their low incidence, these lesions deserve attention because they raise diagnostic and therapeutic problems.

Toussirot E, Le Huédé G, Mougin C, Balblanc JC, Bettinger D, Wendling D. · Department of Rheumatology, University Hospital Jean Minjoz, Besançon, France. · J Rheumatol. · Pubmed #12415596 No free full text.

Abstract: OBJECTIVE: To determine whether hepatitis C virus (HCV) RNA could be detected in the salivary glands of patients with both a diagnosis of Sjögren's syndrome (SS) and HCV infection. METHODS: Five patients with primary SS (European criteria) and chronically infected by HCV and 3 controls (one with primary SS without HCV infection, another with HCV infection without sicca syndrome, and a third without SS and HCV infection) were tested for the presence of HCV-RNA (using reverse transcriptase-polymerase chain reaction) in their saliva, serum, and salivary glands. RESULTS: In the patient group, HCV-RNA was detected in the serum and saliva of all cases and RNA extracted from salivary gland specimens tested positive in 3 cases. In the control group, HCV-RNA was not detected in the serum, saliva, or salivary glands from subjects without HCV infection. Only the control subject with HCV but without sicca syndrome tested positive for the presence of HCV-RNA in the serum, saliva, and salivary gland tissue. CONCLUSION: Our results showed that HCV may propagate and reside within salivary gland tissue, leading to HCV associated sialadenitis or Sjögren's-like syndrome in some cases, a phenomenon that does not seem specific. However, a direct role for HCV in the physiopathology of certain cases of primary SS is suggested.

Zhang SL, Chabod J, Penfornis A, Reviron D, Tiberghien P, Wendling D, Toussirot E. · Blood Transfusion Center Bourgogne/Franche-Comté, UPRES-EA 2284, Besançon, France. · Eur J Immunogenet. · Pubmed #12047361 No free full text.

Abstract: The 'transporter associated with antigen processing' (TAP) gene products are involved in the processing of endogenous peptides that bind to class I molecules. Polymorphism within these genes could alter the level of the immune response, a phenomenon relevant to the development of autoimmune diseases. In this study, we examined the polymorphism of TAP1 and TAP2 genes in patients with rheumatoid arthritis (RA). TAP1 and TAP2 typing was performed for 138 Caucasian RA patients and 100 healthy controls, all originating from eastern France. TAP1 polymorphic residues at positions 333 and 637 and amino acid variants 379, 565, 651 and 665 in the TAP2 gene were found using amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). This method enabled us to determine four TAP1 alleles (TAP1A to TAP1D) and eight TAP2 alleles (TAP2A to TAP2H). All patients and controls had been HLA-DRB1* genotyped. The polymorphic residues TAP1333 and TAP1637 did not show any difference in their distribution between patients and controls. Similar findings were obtained for TAP2379 and TAP2665. However, we found an increased frequency of Thr homozygosity and heterozygosity at position 565 in the TAP2 gene in RA patients (RA vs. controls: 25.3 vs. 14%; P = 0.032; OR = 2.09; CI = 1.01-4.38). Similarly, the prevalence of subjects who were homozygote and heterozygote for Cys651 was increased in the RA group (RA vs. controls: 36.8 vs. 11%; P = 0.02). The dimorphic site TAP2565 defines TAP2D and TAP2E alleles, while the site at position 651 characterizes TAP2F. Thus, we found that TAP2D and TAP2E alleles were more prevalent in RA, but not significantly so (RA vs. controls: TAP2D: 10 vs. 3.6%; P = 0.24; TAP2E: 3.6 vs. 0%; P = 0.19). Similarly, the frequency of TAP2F was higher in RA patients (24.5%) than in controls (11.3%), but this was not significant after correction (P = 0.029; Pcorr = 0.17). Finally, we found no linkage disequilibrium between DRB1* RA-associated alleles and amino acid substitution Thr565 or TAP2D and TAP2E alleles, whereas Cys651 (and TAP2F) was not independent of DRB1*04, a strongly RA-associated allele. Finally, Thr at position 565 in the TAP2 gene was associated with manifestations of disease severity in only a few patients. Examination of TAP1 and TAP2 gene polymorphisms in RA patients revealed an association between a particular amino acid residue, namely Thr565 in the TAP2 gene, and RA. This association was found to be weak and did not seem to be a predictor for the severity of the disease.

Reviron D, Perdriger A, Toussirot E, Wendling D, Balandraud N, Guis S, Semana G, Tiberghien P, Mercier P, Roudier J. · EFS Alpes Méditerranée, Marseilles, France. · Arthritis Rheum. · Pubmed #11263767 links to  free full text

Abstract: OBJECTIVE: Most patients with rheumatoid arthritis (RA) express the shared epitope (SE). It is not known whether SE-negative HLA-DRB1 alleles influence the development of RA. This study examined the influence of SE-negative HLA-DR alleles (DRB1*X) on the development of RA in 3 different French populations. METHODS: HLA-DRB1 alleles were defined by polymerase chain reaction with sequence-specific oligonucleotide hybridization or sequence-specific primers. SE-negative alleles were classified according to the electric charge of their P4 pocket. HLA-DRB1 alleles *0103, *0402, *07, *08, *11 (except *1107), *12, and *13 have a neutral or negative P4 charge and are called DRB1*XP4n. HLA-DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16 have a positive P4 charge and are called DRB1*XP4p. RESULTS: Among the SE-negative subjects, DRB1 genotypes with 1 or 2 DRB1*XP4n alleles were significantly overrepresented in the control subjects compared with the RA patients, whereas DRB1*XP4p/XP4p genotypes were equally represented in the patients and controls. In single-dose SE-positive subjects, SE/XP4n genotypes were equally represented in the patients and controls. However, SE/XP4p genotypes were significantly overrepresented in the RA patients. CONCLUSION: The DRB1*X allele polymorphism influences susceptibility to RA. Alleles that have a neutral or negative electric charge in their P4 pocket (DRB1*XP4n), such as DRB1*0103, *0402, *07, *08, *11 (except *1107), *12, and *13, protect against RA. Alleles that have a positive electric charge in their P4 pocket (DRB1*XP4p), such as DRB1*03, *0403, *0406, *0407, *0901, *1107, *14, *15, and *16, have no influence on the predisposition to RA.