Rheumatoid Arthritis: Wendling D

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.

Wendling D. · No affiliation provided · Joint Bone Spine. · Pubmed #18815066 No free full text.

This publication has no abstract.

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, 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, 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.

Claudepierre P, Wendling D, Cohen JD. · Service de Rhumatologie, CHU Henri Mondor, Créteil. · Presse Med. · Pubmed #16614610 No free full text.

Abstract: Psoriatic arthritis is an inflammatory and possibly destructive form of arthritis. As in rheumatoid arthritis and ankylosing spondylitis, the use of biological therapy in psoriatic arthritis is a therapeutic revolution: both articular and cutaneous efficacy have been shown, and some improvement is visible on radiography. The benefit-risk ratio will improve when we learn to identify more accurately the patients likely to benefit from these treatments.

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.

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.

Wendling D, Jorgensen C. · Service de rhumatologie, centre hospitalier universitaire Jean-Minjoz, 25030 Besançon cedex, France. · Rev Med Interne. · Pubmed #12504237 No free full text.

Abstract: PURPOSE: Interleukin -1 receptor antagonist ( IL-1Ra ) is a new option among biotherapies against rheumatoid arthritis ( RA ). THE AIM: of this review is to recall the rationale of use of IL-1Ra and to analyse the results available in the current literature. CURRENT KNOWLEDGE AND KEY POINTS: Pathophysiological data of RA give a specific position for IL-1 as a potential target for immunotherapy in this disease, confirmed in animal models. Phase II and III studies with IL-1Ra (Anakinra) demonstrated clinical efficacy versus placebo (42% responders in ACR 20 in Anakinra + methotrexate, and 23% in the placebo + methotrexate group at 24 weeks) and a structural effect (slowing of radiological progression at six months). Anakinra has obtained an European license and is indicated in RA not controlled by methotrexate, in daily subcutaneous administration (100 mg/day), in combination with methotrexate. Tolerance is fair; the most frequent side effect is represented by injection site reactions. FUTURE PROSPECTS AND PROJECTS: This ambulatory biotherapy offers new perspectives in combination with other slow acting drugs as well as biologic agents such as anti-TNF, currently under evaluation.

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.

Wendling D. · Service de Rhumatologie, Hôpital Jean-Minjoz, CHU, 1, boulevard Alexander-Fleming, 25030 Besançon Cedex, France. · Ann Med Interne (Paris). · Pubmed #11994686 No free full text.

Abstract: Leflunomide is a new second-line drug for rheumatoid arthritis. This compound with long half-life inhibits proliferation of activated T lymphocytes. Phase III studies have demonstrated a clinical efficacy superior to placebo and identical to comparators (salazopyrine, methotrexate) with a faster onset of response. Improvement of inflammatory paramaters and functional capacity (HAQ) were observed as well as slowing of structural damage evaluated by X-rays. Global tolerance is fair, but possibility of hepatic involvement, although unfrequent, needs a regular survey.

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.

Chopin F, Garnero P, le Henanff A, Debiais F, Daragon A, Roux C, Sany J, Wendling D, Zarnitsky C, Ravaud P, Thomas T. · INSERM U890, Rheumatology Department, University Hospital of St-Etienne, France. · Ann Rheum Dis. · Pubmed #17644538 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is associated with systemic bone loss, subchondral bone erosion and cartilage degradation under the control of pro-inflammatory cytokines, including tumour necrosis factor alpha (TNFalpha). Therefore, we tested the hypothesis that administration of infliximab, an anti-TNFalpha drug in the treatment of RA, would modulate systemic and local bone resorption and reduce cartilage degradation. METHODS: We performed a prospective study of a multicentric cohort of 48 women, mean (SD) age 54.2 (12.1) years old, with severe RA for 11.4 (7.8) years, who started infliximab after failure of other disease-modifying antirheumatic drugs. At baseline and 6, 22 and 54 weeks after initiating Infliximab therapy we measured the following biochemical markers: pro-collagen serum type I N-terminal propeptide (PINP), a marker of bone formation; serum C-terminal cross-linked telopeptide of type I collagen (CTX-I), a marker of cathepsin K-mediated bone collagen degradation believed to reflect systemic bone resorption; serum C-terminal cross-linked telopeptide of type I collagen (ICTP), an index of matrix metalloprotease (MMP) mediated type I collagen degradation reflecting preferential joint metabolism; and urinary CTX-II a biochemical markers of cartilage degradation. Total hip and lumbar spine bone mineral density (BMD) was assessed at baseline, and after 6 and 12 months by dual-energy x-ray absorptiometry (DXA). No patient received bisphosphonates while 77% were under oral glucocorticoids. RESULTS: BMD remained stable over 1 year. Serum CTX-I levels rapidly decreased by 19% and 28% at week 6 and week 22, respectively (analysis of variance (ANOVA) p = 0.032) values returning to pre-treatment level at week 54. By contrast, ICTP levels progressively declined with a maximal 25% decrease at week 54 (ANOVA p = 0.028). By contrast, PINP levels remained stable over time, which led to a 30 to 40% improvement in bone remodelling balance, as assessed by the ratios PINP/CTX and PINP/ICTP (p<0.05). There was no significant change of urinary CTX-II in the whole population, but a slight decrease (ANOVA p = 0.041) in those with pre-treatment levels above the upper limit of normal range. CONCLUSIONS: In summary, the improvement in the formation/resorption marker ratio suggests beneficial systemic and local bone effects of infliximab in patients with RA.

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.

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.

Fautrel B, Guillemin F, Meyer O, de Bandt M, Berthelot JM, Flipo RM, Lioté F, Maillefert JF, Wendling D, Saraux A, Combe B, Le Loët X, Anonymous00044, Anonymous00045, Anonymous00046. · Department of Rheumatology, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. · Arthritis Rheum. · Pubmed #19333993 No free full text.

Abstract: OBJECTIVE: To survey rheumatologists' preferences for the choice of a second-line disease-modifying antirheumatic drug (DMARD) after inadequate response with methotrexate (MTX) therapy in rheumatoid arthritis (RA). METHODS: Thirty-six rheumatologists stated their preferences for RA treatment after inadequate response with MTX therapy (optimal dose at least 6 months). From the initial scenario, we derived 54 vignettes varying by rheumatoid factor or anti-cyclic citrullinated peptide antibody presence, swollen joint count, Disease Activity Score in 28 joints, and structural damage. Respondents stated their preference among 5 therapeutic options: MTX continuation, switch to another conventional DMARD, addition of another conventional DMARD, addition of anakinra, or addition of a tumor necrosis factor (TNF) blocker. Presentation by pairs yielded 10 combinations of strategies for each variant, totaling 540 vignettes; participants evaluated a random sample of 180 vignettes. Determinants of each top-ranked option were analyzed by logistic regression. The compilation of these data served to define a therapeutic algorithm. RESULTS: The responses of 33 rheumatologists were analyzable. Therapeutic preferences corresponded to the top-ranked options. For patients with mild or moderately active RA, either a switch or step-up strategy to another conventional DMARD was top ranked. TNF blockers were preferred for RA patients with high disease activity or progressive structural damage. On the basis of these preferences, we developed a simple decision tree for use in daily clinical practice. CONCLUSION: Our simple, easy-to-use decision tree developed from rheumatologists' preferences for therapy after failure of MTX therapy in RA treatment may guide rheumatologists in daily practice to choose a second-line DMARD.

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.

Wendling D, Balblanc JC, Briançon D, Brousse A, Lohse A, Deprez P, Humbert P, Aubin F. · Rheumatology Department, CHU Jean Minjoz, Minjoz Teaching Hospital, Franche-Comté University, Boulevard Fleming, 25030 Besançon Cedex, France. · Joint Bone Spine. · Pubmed #18329935 No free full text.

Abstract: The widespread use of TNFalpha antagonists in recent years has led to the recognition of paradoxical adverse effects, defined as the onset or exacerbation of disorders that are usually improved by TNFalpha antagonists. Cutaneous psoriasis is an example, of which several cases have been reported. OBJECTIVE: To identify cases of psoriasis onset or exacerbation during TNFalpha antagonist therapy and to look for potential predictive factors. METHODS: We retrospectively reviewed cases of psoriasis onset or exacerbation during TNFalpha antagonist therapy. For each case we recorded the following data: age, sex, underlying disease, nature of the TNFalpha antagonist, effectiveness in improving the underlying disease, history of psoriasis in the patient or family, time to psoriasis development, type of psoriasis (confirmed by an experienced dermatologist), concomitant treatments, whether the TNFalpha antagonist was stopped or continued, and the outcome of the psoriasis. These data were compared to those in the literature. RESULTS: We identified 12 patients, six men and six women, with a mean age of 45.5 years. The TNFalpha antagonist was adalimumab in four patients, etanercept in six patients, and infliximab in two patients. The underlying disease was ankylosing spondylitis in six cases, rheumatoid arthritis in four, and psoriatic arthritis in two. Mean time from treatment initiation to psoriasis was 4.1 months (range, 1-15 months). A previous history of psoriasis in the patient was noted in six cases, including four of the six patients taking etanercept. TNFalpha antagonist therapy was effective on the underlying disease in 11 of the 12 patients. The drug was discontinued in five patients, of whom four experienced resolution of their psoriasis. In the remaining seven patients, the drug was continued and the skin lesions remained unchanged. Most of the patients had psoriasis vulgaris (plaque psoriasis); palmoplantar pustulosis was a feature in five patients. DISCUSSION: Over 40 cases of psoriasis onset or exacerbation during TNFalpha antagonist therapy have been reported in the literature. The prevalence of this adverse effect has been estimated at 1.5-5% of patients taking TNFalpha antagonists. The findings from our case series are consistent with data in the literature. Psoriasis is a class effect that has been reported with all the currently available TNFalpha antagonists. The skin lesions develop within the first few months of therapy. Patients with a wide range of underlying diseases can be affected. Palmoplantar pustulosis is a common feature. A previous history of psoriasis seems more common in patients who experience psoriasis onset or exacerbation during etanercept therapy (four of six patients in our study and 55% in the literature); thus, previous psoriasis may be a risk factor for psoriasis exacerbation during etanercept therapy.

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.

Dichamp I, Bourgeois A, Dirand C, Herbein G, Wendling D. · Department of Virology, CHU Besançon, Franche-Comté University, Besançon, France. · J Rheumatol. · Pubmed #17896809 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is a disease characterized by prolonged production of tumor necrosis factor-alpha (TNF-alpha), which is regulated by the Rel/nuclear factor-kappaB (NF-kappaB) transcription factors. We assessed NF-kappaB activation in peripheral blood mononuclear cells (PBMC), peripheral blood lymphocytes (PBL), and monocytes from patients with RA, patients with ankylosing spondylitis (AS), and healthy subjects. METHODS: NF-kappaB activation was determined by electrophoretic mobility shift assays and by Western blotting in PBMC, monocytes, and PBL isolated from peripheral blood of patients with RA, patients with AS, and healthy subjects and determined after ex vivo pretreatment of PBMC, PBL, and monocytes of patients with RA and healthy subjects with infliximab and with etanercept. RESULTS: Enhanced NF-kappaB activation was observed in monocytes, PBL, and PBMC isolated from patients with RA, but not in PBMC, PBL, and monocytes of patients with AS and healthy subjects. The NF-kappaB complex was composed of p50 and p65 subunits and its activation required inhibitor of NF-kappaBalpha degradation. We observed a positive correlation between the NF-kappaB activation in monocytes, PBL, and PBMC, and TNF-alpha levels in peripheral blood of patients with RA. Ex vivo treatment with infliximab and etanercept decreased NF-kappaB activation in monocytes of patients with RA, but not in PBL and PBMC, and not in healthy subjects. CONCLUSION: Our results indicate a role for NF-kappaB activation and TNF-alpha in the activation of monocytes of patients with RA, and suggest an important role of circulating monocytes in RA pathogenesis.

Meyer O, de Bandt M, Berthelot JM, Cantagrel A, Combe B, Fautrel B, Flipo RM, Lioté F, Maillefert JF, Saraux A, Wendling D, Guillemin F, Le Loët X, Anonymous00174. · Department of Rheumatology, AP-HP, Bichat Paris 7 University Hospital, CHU Bichat, 46 rue Henri Huchard, 75018 Paris, France. · Joint Bone Spine. · Pubmed #17194614 No free full text.

Abstract: BACKGROUND: The objective was to develop a clinical practice format for choosing a second-line disease-modifying anti-rheumatic drug (DMARD) after a 6-month course of a first-line DMARD in patients with early RA. METHODS: A panel of 34 experts selected treatment option from various scenarios using the Thurstone pairwise method. The experts had to choose between two proposed DMARDs without proposing other options. The scenarios were obtained using the three items: DAS28, rheumatoid factor status and radiographic structural damage. A sample of 240 among 480 scenarios for each expert was taken at random. Responses given by at least 20% of the experts were considered pertinent. RESULTS: Recommendations for choosing a second DMARD for early RA after failure of a 6-month course of a first-line DMARD were established according to 4 parameters: type of first-line DMARD, activity, RF status and radiographic joint damage. The results of this study suggest that in patients with early RA who fail a 6-month course of first-line DMARD therapy, the best options may be addition of corticosteroid when disease activity is moderate to high and switching to a biologic agent when further radiographic joint damage occurs, particularly in patients with positive tests for RF. CONCLUSION: Although our scenarios did not include step-up (add instead of substitute) strategies, except for corticosteroids, we feel that the format presented here can optimise the management of patients with early RA seen in clinical practice.

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.