Rheumatoid Arthritis: Breban M

Bernardeau C, Dernis-Labous E, Blanchard H, Lamarque D, Breban M. · No affiliation provided · Joint Bone Spine. · Pubmed #11808980 No free full text.

Abstract: Nitric oxide (NO) is attracting considerable interest because it mediates many functions. This gas is ubiquitously produced in the body by three enzymes, called NO synthases. Two NO synthases are constitutively expressed, one in the nervous system and the other in the blood vessels, where it regulates tissue perfusion. The third NO synthase can be induced by several stimuli (bacterial endotoxins, cytokines), most notably in inflammatory cells and chondrocytes. The effects of NO produced by the inducible NO synthase range from T-cell response modulation to formation of free radicals responsible fortissue damage and cartilage matrix degradation. Administration of NO synthase inhibitors in animal models of arthritis yields ambiguous effects, often with prevention of arthritis, but sometimes with worsening of established arthritis. The data available to date do not support the use of such inhibitors in the treatment of human arthritis.

Braun J, Breban M, Maksymowych WP. · Rheumazentrum Ruhrgebiet, Landgrafenstr.15, 44652, Herne, Germany. · Best Pract Res Clin Rheumatol. · Pubmed #12406431 No free full text.

Abstract: The therapeutic options for patients suffering from the more severe forms of spondyloarthritis (SpA) have been rather limited in recent decades. There is now accumulating evidence that anti-tumour necrosis factor (anti-TNF) therapy is highly effective in SpA, especially in ankylosing spondylitis (AS) and psoriatic arthritis (PsA). Based on the data recently published on more than 200 AS patients, and more than 100 PsA patients, this treatment seems to be even more effective than it is in rheumatoid arthritis (RA). The two major anti-TNF-alpha agents currently available, infliximab (Remicade) and etanercept (Enbrel), are approved for the treatment of RA in Europe and in the USA. The situation in SpA is different from RA because there is an unmet medical need, especially in AS, because disease-modifying anti-rheumatic therapy is not available for severely affected patients. Thus, TNF blockers might even be considered first-line immunosuppressive treatment in patients with active AS who are not sufficiently treated with non-steroidal anti-inflammatory drugs (NSAIDs). For infliximab, a dose of 5mg/kg was required, and intervals between 6 and 12 weeks were necessary for constant suppression of disease activity - a major aim also for long-term treatment. However, it remains to be shown whether patients benefit from long-term therapy and whether radiological progression and ankylosis can be stopped. The optimal doses of infliximab might well be determined individually. Allergic reactions and increased susceptibility to tuberculosis are rare side-effects which need to be recognized early. As it stands now, the benefits of anti-TNF therapy in AS seem to outweigh these shortcomings. The efficacy of etanercept was first demonstrated in PsA. A double-blind study has now been performed in AS - with similar results. There is preliminary evidence that both agents also work in other SpA such as undifferentiated SpA. Hopefully, both agents will be approved soon for the short-term treatment of severe SpA. In parallel, studies should be performed to document the long-term efficacy and safety of this treatment.

Maksymowych WP, Breban M, Braun J. · Department of Medicine, University of Alberta, Edmonton, Alberta, Canada T6G 2S2. · Best Pract Res Clin Rheumatol. · Pubmed #12406430 No free full text.

Abstract: In contrast to rheumatoid arthritis (RA), the concept of disease modification in ankylosing spondylitis (AS) remains to be clarified. Endpoint measures employed in AS trials primarily assess features related to symptomatology while endpoints considered more relevant to the concept of disease modification, such as spinal mobility, acute-phase reactants and radiological progression, either lack sensitivity to change or have not been comprehensively validated. NSAIDs alleviate symptoms of AS but most trials have been short term, precluding meaningful conclusions regarding disease modification. Among disease-modifying therapies used in RA, sulfasalazine has been studied in several controlled trials mostly in patients with longstanding disease, effect sizes being small and limited to those with peripheral synovitis. No conclusions can be drawn from the limited studies evaluating methotrexate.

Braun J, Sieper J, Breban M, Collantes-Estevez E, Davis J, Inman R, Marzo-Ortega H, Mielants H. · Rheumazentrum Ruhrgebiet, Landgrafenstrasse 15, 44652 Herne, Germany. · Ann Rheum Dis. · Pubmed #12381511 links to  free full text

Abstract: The conventional approach to treatment of patients with spondyloarthritis (SpA), particularly ankylosing spondylitis (AS), has serious limitations, adding a sense of urgency to the evaluation of new treatments for these rheumatic disorders. Tumour necrosis factor alpha (TNFalpha) is a cytokine that has been shown to mediate inflammatory and regulatory activities in SpA and other immune mediated diseases, including other arthritides and inflammatory bowel disease. Positive results have been reported in several international open label and randomised controlled trials of infliximab and etanercept, the two main biological agents targeting TNFalpha, which have included approximately 300 patients with SpA. Specifically, TNFalpha-directed therapy resulted in significant improvements in disease activity, function, and quality of life in these patients, most of whom had AS and received infliximab. Preliminary evidence from open label, long term extension trials suggests clinical benefit with continued use. Serious side effects were rare and consistent with experience from patient groups receiving infliximab or etanercept treatment for inflammatory bowel disease or rheumatoid arthritis. Together, these findings herald an age of more effective treatment of patients with AS with anti-TNFalpha and other emerging biological agents.

D'Agostino MA, Breban M. · Università Cattolica del Sacro Coore, C.I.C., Rome, Italy. · Joint Bone Spine. · Pubmed #12102270 No free full text.

Abstract: During the last decade, articular ultrasonography (US) has been found effective in evaluating inflammatory, degenerative, and traumatic abnormalities of articular and periarticular tissues. In clinical practice, US used in combination with a thorough clinical evaluation can help rheumatologists to confirm or to refute diagnostic hypotheses. US is safer than computed tomography (CT), an advantage shared by magnetic resonance imaging (MRI). As compared to CT and MRI, US is less expensive; in addition, it can be performed immediately, for several joints, as often as needed. Furthermore, US allows dynamic studies. Several articles published in rheumatology journals emphasize the value of US in patients with musculoskeletal diseases. The present review article discusses the indications, efficacy, and limitations of articular US.

Breban M, Dougados M, Picard F, Zompi S, Marolleau JP, Bocaccio C, Heshmati F, Mezieres M, Dreyfus F, Bouscary D. · Cochin Hospital, Université René Descartes, Paris, France. · Arthritis Rheum. · Pubmed #10555020 links to  free full text

Abstract: OBJECTIVE: To evaluate the feasibility, safety, and efficacy of intensified-dose cyclophosphamide (ID-CYC), followed by granulocyte colony-stimulating factor (G-CSF) administration for collection of peripheral blood hematopoietic stem cells (HSC), for patients with severe, refractory rheumatoid arthritis (RA). METHODS: Four patients with severe refractory RA were enrolled in this open study. They received a single infusion of CYC (4 gm/m2) at day 0 followed by G-CSF (5 microg/kg/day) from day 6 until the last day of leukapheresis (performed at the time of hematopoietic recovery) to harvest peripheral blood HSC. Patients were monitored for disease activity, adverse effects, and hematopoietic reconstitution following this procedure. RESULTS: For all patients, administration of ID-CYC induced an early, dramatic improvement of disease activity. Long-term followup indicates that partial disease relapse was observed for all patients. No adverse effect was directly attributable to the treatment procedure. For most patients, HSC collection was sufficient to provide a graft enriched in CD34+ cells by positive selection as well as an unselected rescue graft. CONCLUSION: Patients with severe, refractory RA can benefit from ID-CYC. This procedure, followed by G-CSF administration, appears safe and technically suitable. In addition, it allows immediate improvement of RA activity that can occasionally persist beyond 6 months.

Baeten D, Kruithof E, Breban M, Tak PP. · Clinical Immunology and Rheumatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Arthritis Rheum. · Pubmed #18311807 links to  free full text

Abstract: The highly effective treatment of rheumatoid arthritis by B cell depletion and the presence of B cells in the peripheral and axial lesions of patients with spondylarthritis (SpA) raise the question as to whether B lymphocytes could also be an appropriate therapeutic target in the latter disease. We describe 2 male HLA-B27-positive patients who had active SpA despite absence of B cells. One patient developed SpA with sacroiliitis and asymmetric oligoarthritis after having been diagnosed as having severe Bruton agammaglobulinemia. Since extensive investigations excluded an infectious origin of the SpA, this case illustrates that functional B cells and/or gamma globulins are not strictly required for SpA pathogenesis. The second patient had severe axial and peripheral SpA that was treated successfully with etanercept. After discontinuation of etanercept treatment because of non-Hodgkin's B cell lymphoma, both axial and peripheral SpA symptoms relapsed rapidly, and this exacerbation of articular disease activity was not modulated by successful B cell depletion therapy for the lymphoma. Although case reports have obvious limitations, our clinical observations provide evidence that active SpA can occur in the absence of functional mature B cells and thus emphasize the need for systematic studies of the exact role and function of B lymphocytes in this disease.

Devauchelle V, Essabbani A, De Pinieux G, Germain S, Tourneur L, Mistou S, Margottin-Goguet F, Anract P, Migaud H, Le Nen D, Lequerré T, Saraux A, Dougados M, Breban M, Fournier C, Chiocchia G. · Institut Cochin, Département d'Immunologie, 27 rue du Faubourg Saint-Jacques, 75674 Paris Cedex 14, France. · J Immunol. · Pubmed #17056579 links to  free full text

Abstract: We previously compared by microarray analysis gene expression in rheumatoid arthritis (RA) and osteoarthritis (OA) tissues. Among the set of genes identified as a molecular signature of RA, clusterin (clu) was one of the most differentially expressed. In the present study we sought to assess the expression and the role of CLU (mRNA and protein) in the affected joints and in cultured fibroblast-like synoviocytes (FLS) and to determine its functional role. Quantitative RT-PCR, Northern blot, in situ hybridization, immunohistochemistry, and Western blot were used to specify and quantify the expression of CLU in ex vivo synovial tissue. In synovial tissue, the protein was predominantly expressed by synoviocytes and it was detected in synovial fluids. Both full-length and spliced isoform CLU mRNA levels of expression were lower in RA tissues compared with OA and healthy synovium. In synovium and in cultured FLS, the overexpression of CLU concerned all protein isoforms in OA whereas in RA, the intracellular forms of the protein were barely detectable. Transgenic overexpression of CLU in RA FLS promoted apoptosis within 24 h. We observed that CLU knockdown with small interfering RNA promoted IL-6 and IL-8 production. CLU interacted with phosphorylated IkappaBalpha. Differential expression of CLU by OA and RA FLS appeared to be an intrinsic property of the cells. Expression of intracellular isoforms of CLU is differentially regulated between OA and RA. We propose that in RA joints, high levels of extracellular CLU and low expression of intracellular CLU may enhance NF-kappaB activation and survival of the synoviocytes.

Hamdi H, Mariette X, Godot V, Weldingh K, Hamid AM, Prejean MV, Baron G, Lemann M, Puechal X, Breban M, Berenbaum F, Delchier JC, Flipo RM, Dautzenberg B, Salmon D, Humbert M, Emilie D, Anonymous00131. · INSERM UMR-S764, Service d'Hépato-Gastro-Entérologie, Hôpital Antoine Béclère, Assistance Publique-Hôpitaux de Paris, Institut Paris-Sud sur les Cytokines, Université Paris-Sud, INSERM U764, 32 rue des Carnets, 92140, Clamart, France. · Arthritis Res Ther. · Pubmed #16859506 links to  free full text

Abstract: Reactivation of latent Mycobacterium tuberculosis (Mtb) infection is a major complication of anti-tumour necrosis factor (TNF)-alpha treatment, but its mechanism is not fully understood. We evaluated the effect of the TNF antagonists infliximab (Ifx), adalimumab (Ada) and etanercept (Eta) on anti-mycobacterial immune responses in two conditions: with ex vivo studies from patients treated with TNF antagonists and with the in vitro addition of TNF antagonists to cells stimulated with mycobacterial antigens. In both cases, we analysed the response of CD4+ T lymphocytes to purified protein derivative (PPD) and to culture filtrate protein (CFP)-10, an antigen restricted to Mtb. The tests performed were lymphoproliferation and immediate production of interferon (IFN)-gamma. In the 68 patients with inflammatory diseases (rheumatoid arthritis, spondylarthropathy or Crohn's disease), including 31 patients with a previous or latent tuberculosis (TB), 14 weeks of anti-TNF-alpha treatment had no effect on the proliferation of CD4+ T lymphocytes. In contrast, the number of IFN-gamma-releasing CD4+ T lymphocytes decreased for PPD (p < 0.005) and CFP-10 (p < 0.01) in patients with previous TB and for PPD (p < 0.05) in other patients (all vaccinated with Bacille Calmette-Guérin). Treatments with Ifx and with Eta affected IFN-gamma release to a similar extent. In vitro addition of TNF antagonists to CD4+ T lymphocytes stimulated with mycobacterial antigens inhibited their proliferation and their expression of membrane-bound TNF (mTNF). These effects occurred late in cultures, suggesting a direct effect of TNF antagonists on activated mTNF+ CD4+ T lymphocytes, and Ifx and Ada were more efficient than Eta. Therefore, TNF antagonists have a dual action on anti-mycobacterial CD4+ T lymphocytes. Administered in vivo, they decrease the frequency of the subpopulation of memory CD4+ T lymphocytes rapidly releasing IFN-gamma upon challenge with mycobacterial antigens. Added in vitro, they inhibit the activation of CD4+ T lymphocytes by mycobacterial antigens. Such a dual effect may explain the increased incidence of TB in patients treated with TNF antagonists as well as possible differences between TNF antagonists for the incidence and the clinical presentation of TB reactivation.

d'Agostino MA, Ayral X, Baron G, Ravaud P, Breban M, Dougados M. · Cochin Hospital, and Université René Descartes, Paris, France. · Arthritis Rheum. · Pubmed #15818652 links to  free full text

Abstract: OBJECTIVE: To assess the impact of ultrasonography (US) on local corticosteroid (CS) injections of painful ankle, hindfoot, and midfoot in chronic inflammatory diseases. METHODS: Consecutive patients with chronic rheumatic diseases admitted to the hospital for local CS injections of painful ankle, hindfoot, or midfoot were enrolled in this study. Clinical and radiographic evaluation was performed by the physician in charge of CS injections, and US examination was performed by an independent examiner blinded to the clinical and radiologic findings. According to a randomized weekly-periods design, the physician planned CS injections either aware (G1 group) or unaware (G2 group) of US results. In the latter case, he was nonetheless informed of US results after he had performed the injections. Impact of this information on the treatment planning was assessed in all cases. Prognostic impact of US was also evaluated by comparing the change in global assessment of efficacy of CS injections, in activity of the disease, and in the Western Ontario and McMaster Universities (WOMAC) subscales after 1 and 3 months, between G1 and G2 groups. RESULTS: The knowledge of US findings led the physician to change his decision of local CS injections in 56 (82%) of 68 patients studied. Among 1,131 assessed sites, by clinical, radiographic, and US evaluation, injection was cancelled in 37 (15%) of 242 proposed sites, whereas it was decided in 74 (8%) additional sites. After 1 month, there was an improvement in G1 as compared with G2 groups. The mean +/- SD change in WOMAC physical function subscale was 15.6 +/- 17.5 in G1 versus 8 +/- 13 in G2 (P = 0.0305). After 3 months, only the global assessment of efficacy of CS injections was statistically greater in G1 than in G2 group (P = 0.0170). CONCLUSION: US frequently led the physician to change his diagnosis of inflammatory lesions in painful foot, and consequently his planning of CS injections. Moreover, US could improve the response to local treatment.

Devauchelle V, Marion S, Cagnard N, Mistou S, Falgarone G, Breban M, Letourneur F, Pitaval A, Alibert O, Lucchesi C, Anract P, Hamadouche M, Ayral X, Dougados M, Gidrol X, Fournier C, Chiocchia G. · Institut Cochin, Paris, France. · Genes Immun. · Pubmed #15496955 No free full text.

Abstract: This study was undertaken to evaluate the possibility to obtain a molecular signature of rheumatoid arthritis (RA) comparatively osteoarthritis (OA), and to lay the bases to develop new diagnostic tools and identify new targets. Microarray technology was used for such an analysis. The gene expression profiles of synovial tissues from patients with confirmed RA, and patients with OA were established and compared. A set of 63 genes was selected, based, more specifically, on their overexpression or underexpression in RA samples compared to OA. Results for six of these genes have been verified by quantitative PCR using both samples identical to those used in the microarray experiments and entirely separate samples. Expression profile of the 48 known genes allowed the correct classification of additional RA and OA patients. Furthermore, the distinct expression of three of the selected genes was also studied by quantitative RT-PCR in cultured synovial cells. Detailed analysis of the expression profile of the selected genes provided evidence for dysregulated biological pathways, pointed out to chromosomal location and revealed novel genes potentially involved in RA. It is proposed that such an approach allows valuable diagnosis/prognostics tools in RA to be established and potential targets for combating the disease to be identified.

D'Agostino MA, Maillefert JF, Said-Nahal R, Breban M, Ravaud P, Dougados M. · Service de Rhumatologie B, Hôpital Cochin, 27 rue du Faubourg Saint Jacques, 75014 Paris, France. · Ann Rheum Dis. · Pubmed #15361388 links to  free full text

Abstract: BACKGROUND: Ultrasonography allows assessment of soft tissue structures and has become a valued tool for diagnosing synovitis. OBJECTIVE: To assess the learning curve for ultrasonography in evaluating synovitis of the small joints in rheumatoid arthritis. METHODS: Metacarpophalangeal (MCP), metatarsophalangeal (MTP), and proximal interphalangeal (PIP) joints were evaluated using ultrasonography (Esaote AU 5 Epi, linear probe 10-13 MHz) by four rheumatologists, the first being experienced (senior), the others having no (fellows 1 and 2) or little (fellow 3) experience in ultrasonography. For each fellow, the learning curve was divided into blocks. In each block the fellow examined five consecutive patients with the senior; then, blinded to the senior's results, two further patients alone (seven patients examined per block). For each evaluation, the MCP, PIP, and MTP joints were individually tagged as having synovitis or not. The ultrasonography results were compared between fellow and senior for the two last patients of each block, using proportions of agreement and kappa statistics. RESULTS: 70 patients were evaluated (seven practice patients, followed by nine blocks). For fellows 1 and 2, the proportions of agreement were respectively 42% and 47% (kappa = 0 and 0) at the first evaluation, and rose progressively to 82% and 82% (kappa = 0.63 and 0.62) at the ninth evaluation. For fellow 3, initially good results were followed by decreased accuracy. CONCLUSIONS: Detecting synovitis of the MCP, PIP, and MTP joints using ultrasonography can be done accurately by rheumatologists initially not experienced in this technique. At least 70 examinations were necessary to develop competence.

D'Agostino MA, Said-Nahal R, Hacquard-Bouder C, Brasseur JL, Dougados M, Breban M. · Cochin Hospital, INSERM, CNRS, Université René Descartes, AP-HP, Paris, France. · Arthritis Rheum. · Pubmed #12571863 links to  free full text

Abstract: OBJECTIVE: To assess the prevalence and severity of peripheral enthesitis among the different subtypes of spondylarthropathy (SpA) by using ultrasonography (US) in B mode with power Doppler. METHODS: One hundred sixty-four consecutive patients with SpA (according to the criteria of the European Spondylarthropathy Study Group) and 64 control patients (34 with mechanical low back pain [MBP] and 30 with rheumatoid arthritis [RA]) underwent US examination of major entheses of their limbs. Particular attention was given to the detection of vascularization at the following sites: cortical bone insertion of entheses, junction between tendon and entheses, body of tendon, and bursa. RESULTS: Abnormal US findings consistent with at least one enthesitis were observed in 161 of 164 SpA patients (98%), affecting 1,131 of 2,952 entheses examined (38%). In contrast, only 132 of 1,152 entheses (11%) were found to be abnormal in 33 of 64 control patients (52%). US enthesitis was most commonly distributed in the distal portion of the lower limbs, irrespective of SpA subtype and of skeletal distribution of clinical symptoms. None of the abnormal entheses in control patients showed vascularization, compared with 916 of 1,131 abnormal entheses in SpA patients (81%), where it was always detected at the cortical bone insertion and sometimes also in the bursa. In SpA patients, the US pattern depended on the clinical presentation, with a higher prevalence of the most severe stages in those with peripheral forms. CONCLUSION: US in B mode combined with power Doppler allowed the detection of peripheral enthesitis in a majority of SpA patients, but not in MBP or RA patients. The presence of entheseal involvement was independent of SpA subtype, but its degree of severity appeared to be greater in peripheral forms. US could be very useful for both the diagnosis and the assessment of SpA activity.

Miceli-Richard C, Zouali H, Lesage S, Thomas G, Hugot JP, Said-Nahal R, Breban M. · Foundation Jean Dausset/CEPH, Paris, France. · Arthritis Rheum. · Pubmed #12115249 links to  free full text

This publication has no abstract.

Maillefert JF, Muller G, Falgarone G, Bour JB, Ratovohery D, Dougados M, Tavernier C, Breban M. · Department of Rheumatology, René Descartes University, AP-HP, Cochin Hospital, Paris, France. · Ann Rheum Dis. · Pubmed #12079907 links to  free full text

Abstract: BACKGROUND: Various viruses have been implicated in the cause and pathogenesis of rheumatoid arthritis (RA). Hepatitis C virus (HCV) infection, which has been recognised as a cause of some autoimmune diseases, and which has been described as sometimes presenting with rheumatic manifestations indistinguishable from RA, might be a candidate. OBJECTIVE: To evaluate the prevalence of HCV infection in patients with RA. METHODS: Consecutive patients with RA admitted to hospital in two departments of rheumatology were prospectively studied. Patients' serum samples were screened for the presence of anti-HCV antibodies. Patients with positive serology were further evaluated for the presence of HCV ribonucleic acid by reverse transcriptase polymerase chain reaction (RT-PCR). RESULTS: 309 patients (232 women, 77 men, mean age (SD) 54.1 (14.8) years) were studied. Their mean (SD) disease duration was 74.1 (91) months. Tests for rheumatoid factors and antinuclear antibodies were positive in 213 (69%) and 114 (37%) of the patients respectively. Systemic vasculitis was found in 12 (4%) of the patients. Mean erythrocyte sedimentation rate was 36.4 (SD 30.5) mm at the first hour (normal <10 mm) and C reactive protein was 36.8 (SD 45.8) mg/l (normal range <5 mg/l), respectively, with 181(58.6%) of patients considered as having active disease. Aspartate transaminases were increased in 14 (4%) patients, and alkaline phosphatase in 14 (4%). A positive anti-HCV serology was found in two (0.65%) patients, including one with a previously diagnosed HCV infection. HCV RNA was positive by RT-PCR in one of those two patients. CONCLUSION: A 0.65% prevalence of past or active HCV infection was found in patients with RA, which did not differ from the prevalence of HCV in the general French population. This result does not support the participation of HCV infection in the pathogenesis of RA.