Rheumatoid Arthritis: Allanore Y

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

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

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

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

Assous N, Gossec L, Dougados M, Kahan A, Allanore Y. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #17631755 No free full text.

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Allanore Y, Sellam J, Batteux F, Job Deslandre C, Weill B, Kahan A. · Rheumatology A Department, Paris V University, Cochin Hospital, AP-HP Paris, France. · Clin Exp Rheumatol. · Pubmed #15638051 No free full text.

Abstract: OBJECTIVES: To investigate autoantibody induction in rheumatoid arthritis (RA) patients treated with infliximab. METHODS: We included 59 refractory RA patients treated with infliximab in combination with low-dose prednisone and methotrexate or leflunomide. We tested the sera of the patients for antinuclear antibodies (ANA), rheumatoid factor (RF), anti double-stranded DNA antibodies (anti dsDNA), anti-histone and anti-extractable nuclear antigen antibodies (aENA) at baseline and before infusion at weeks 6 and 30. Infliximab, initiated at a dose of 3 mg/kg, was increased to 5 mg/kg if insufficient improvement was observed after three infusions. RESULTS: At week 6, only the frequency of anti-histone IgM antibody-positive patients had significantly increased (19 vs 42%, p = 0.009). At week 30, the frequency of patients with ANA had increased from 29% to 69% (p < 0.001), that of patients with anti-dsDNA antibodies had increased from 0% to 3% for IgG (NS) and from 0% to 32% for IgM (p < 0.001); the frequency of antihistone IgG detection had increased from 22% to 32% (p = 0.04) and that of IgM detection, from 18% to 79% (p < 0.001). No lupus-like syndrome was observed. RF decreased significantly (87 IU to 52.5 IU, from baseline to week 30; p < 0.001). No significant difference was observed between the 16 non-responders and the responders, in terms of autoantibody status at baseline and changes with infliximab therapy. CONCLUSION: Infliximab therapy lead to the selective and delayed induction of autoantibodies. This induction was not associated with clinical symptoms until week 30 and did not differ between responders and non-responders.

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

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

Thelier N, Assous N, Job-Deslandre C, Meyer O, Bardin T, Orcel P, Lioté F, Dougados M, Kahan A, Allanore Y. · Department of Rheumatology A, Paris Descartes University, Paris, France. · J Rheumatol. · Pubmed #18634144 No free full text.

Abstract: OBJECTIVE: To analyze the pattern of osteoarticular lesions in patients with sarcoidosis hospitalized in 4 rheumatology departments. METHODS: We carried out a systematic retrospective analysis of cases with sarcoidosis admitted in the last 10 years, using hospital databases. Two distinct groups were defined from the outset: patients with Löfgren's syndrome (LS) or sarcoid rheumatism (SR). We assessed the following items: distribution of arthritis, chronicity, systemic manifestations, biochemical and immunological measures. RESULTS: We included 100 patients (75% women); 43% had LS and 57% SR. Osteoarticular symptoms revealed the disease in 85% of patients. The patients in the LS group were younger than those in the SR group (41 +/- 9 vs 48 +/- 13 yrs; p < 0.006) and were more likely to have oligoarthritis involving ankles (58% vs 32%; p = 0.04) and high C-reactive protein concentrations (63% vs 33%; p < 0.005). Patients with SR presented osteoarticular symptoms in the form of oligoarthritis (32%), polyarthritis (32%), bony erosion in 8/57 (14%), and osteitis in 9/57 (16%). Lung interstitial involvement was more frequent in the SR group than in the LS group (38% vs 18%; p = 0.03). Chronic polyarthritis was associated with the detection of rheumatoid factor (p = 0.004). Osteitis occurred in older patients (p = 0.02). CONCLUSION: SR was the most frequent manifestation leading to hospitalization; it was characterized by oligoarthritis and polyarthritis and associated with interstitial lung involvement. Osseous involvement occurred in a quarter of SR patients with similar frequency of erosions targeting the distal small bones and osteitis. These latter occurred at a later age.

Assous N, Gossec L, Dieudé P, Meyer O, Dougados M, Kahan A, Allanore Y. · Department of Rheumatology A and Rheumatology B, Paris Descartes University, Medical Faculty, Cochin Hospital, AP-HP, Paris, France. · J Rheumatol. · Pubmed #18176989 No free full text.

Abstract: OBJECTIVE: Rituximab has been shown to be effective in refractory rheumatoid arthritis (RA) in randomized controlled trials, allowing approval by health agencies. Our aim was to assess in routine care the effects of rituximab in patients with RA who had experienced an inadequate response to anti-tumor necrosis factor-alpha (TNF-alpha) agents or had a contraindication to these drugs. METHODS: An observational retrospective study was conducted. Rituximab (1000 mg intravenous infusion on Days 1 and 15) was administered with concomitant methotrexate therapy. Responses defined according to the European League Against Rheumatism (EULAR criteria) were assessed at Week 24. RESULTS: Fifty patients were included: 30 had inadequate response to anti-TNF-alpha and 20 had contraindication to anti-TNF-a drugs. EULAR response was observed in 82%, good response in 36% (including remission in 12%), moderate response in 46%, and no response in 18%. One infusion-related reaction and 2 pulmonary infections occurred. Eleven of the 50 patients (22%) experienced flare and received retreatment with rituximab at 6 months. Thirty additional patients had flare after 6 months and the median delay for retreatment among the 41 responders was 9 (range 6 24) months. No difference regarding efficacy or tolerance of rituximab was observed according to previous inadequate response or contraindication to anti-TNF. CONCLUSION: A single cycle of rituximab, in combination with continued methotrexate, provided significant improvement in disease activity at Week 24, with good tolerance, in patients with severe and active RA despite anti-TNF-alpha agents and/or with contraindication to these drugs, in this daily practice study.

Meune C, Wahbi K, Assous N, Weber S, Kahan A, Allanore Y. · Department of Cardiology, Paris Descartes University, Medical School, Cochin Hospital, Paris, France. · J Rheumatol. · Pubmed #17787044 No free full text.

Abstract: OBJECTIVE: To determine the sensitivity and accuracy of tissue-Doppler echocardiography (TDE) to assess myocardial contractility. Heart failure is one of the determinants of the excess in mortality in patients with rheumatoid arthritis (RA). METHODS: Consecutive RA patients with normal clinical cardiac examination were prospectively included and compared to 27 controls. All underwent conventional echocardiography, and systolic and diastolic strain rate (SR) were determined by TDE. RESULTS: Twenty-seven patients with RA were included (mean age 50 +/- 10 yrs, disease duration 8 +/-6 yrs). Mean disease activity score was 4.3 +/- 1.6, C-reactive protein 23 +/- 32 mg/l. When compared to controls (50 +/- 9 yrs), patients with RA had increased left ventricular mass (99 +/- 24 vs 80 +/- 25 g/m2, p = 0.009), and there was a trend for left atrial enlargement (31 +/- 3 vs 29 +/- 6 mm, p = 0.06). Fractional shortening and systolic SR did not differ between groups. Diastolic function, as estimated by the E/A Doppler velocity ratio was similar in both groups (p = 0.18). However, diastolic SR was strikingly reduced in patients with RA versus controls (3.7 +/- 1.3 vs 5.5 +/- 1.1s-1, p < 0.001) with 18/27 patients with RA having marked reduced diastolic SR (SR < 4s-1). None of the RA characteristics was associated with significant differences in TDE measurements. CONCLUSION: TDE identifies impaired diastolic function in patients with RA that may not be detected by conventional measurements.

Allanore Y, Seror R, Chevrot A, Kahan A, Drapé JL. · René Descartes University, and Service de Rheumatologie A, Hôpital Cochin, 27 Rue du Faubourg St. Jacques, 75014 Paris, France. · Arthritis Rheum. · Pubmed #17665441 links to  free full text

Abstract: OBJECTIVE: Impairment of the microcirculation is a cardinal feature of systemic sclerosis (SSc). Magnetic resonance angiography (MRA) has improved the assessment of vascular lesions of the hand. The aim of this study was to evaluate vascular abnormalities in the hands of patients with SSc, using MRA. METHODS: Thirty-eight patients with SSc were compared with 7 healthy subjects and 7 patients with rheumatoid arthritis. Among patients with SSc, the mean +/- SD age was 52 +/- 14 years, the mean +/- SD Health Assessment Questionnaire (HAQ) score was 0.9 +/- 0.8, and the mean +/- SD systolic pulmonary artery pressure (PAP) was 32.2 +/- 8.4 mm Hg. Ten patients had a history of digital ulcers. The MRA protocol consisted of 4 successive acquisitions, each lasting 52 seconds, of 3-dimensional coronal cross-sectional images after gadolinium injection. The primary criteria were distality and quality of arterial opacification, avascular areas, and venous return. RESULTS: Thirty-five of the patients with SSc (92%) had at least 1 true digital artery that did not reach the first phalanx at the initial arterial analysis, and 23 patients (61%) had > or =4 damaged arteries. Twenty-eight patients (74%) had thin arteries, and 20 patients (53%) had >1 avascular area. Nearly all patients (35 of 38 [92%]) had abnormal venous return, and a lack of visible venous return was observed in 16 patients (42%). Results for all of the control subjects were considered normal. Digital ulcers were more frequently observed in patients with SSc who had > or =4 damaged proper digital arteries compared with other patients (P = 0.003), the HAQ score was associated with thin-caliber arteries (P = 0.04), and systolic PAP was associated with tissue enhancement secondary to ischemia (P = 0.04). CONCLUSION: These results show the substantial vascular involvement in SSc. Lesions were diffuse and involved both arterial and venous vessels of small caliber as well as the microcirculation.

Allanore Y, Batteux F, Avouac J, Assous N, Weill B, Kahan A. · Rheumatology A and Immunology departments, René Descartes University, Medical School, Cochin Hospital, Assistance Publique Hôpitaux de Paris, France. · Clin Exp Rheumatol. · Pubmed #17417992 No free full text.

Abstract: OBJECTIVE: Contradictory results have been reported regarding vasculogenesis in systemic sclerosis (SSc). Our aim was to investigate bone marrow-derived circulating endothelial precursors (EPCs) and activated circulating endothelial cells (CECs) in SSc patients. METHODS: Peripheral blood from consecutive patients with SSc hospitalised for systemic follow-up was analysed and compared with blood from patients with active refractory rheumatoid arthritis (RA) and osteoarthritis (OA). EPCs were quantified by cell sorting and flow cytometry and were identified as circulating CD34+CD133+ cells. Activated CECs were defined as CD105+CD62+CD105+CD102+CD105+CD106+ cells. RESULTS: Patients with SSc had higher putative EPC levels than OA patients, but lower levels than RA patients. In SSc patients, EPC levels increased with European disease activity score. Activated CEC levels were high in SSc patients and RA patients, but not correlated with EPC levels. CONCLUSION: These results together and previous data suggest that EPCs may be recruited during active vascular disease but that the sustained ischaemic conditions of SSc may eventually lead to EPCs depletion.

Caramella C, Avouac J, Sogni P, Puéchal X, Kahan A, Allanore Y. · Service de Rhumatologie A, Université René Descartes, Faculté de Médecine, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, 75014 Paris, France. · Joint Bone Spine. · Pubmed #17369071 No free full text.

Abstract: Primary biliary cirrhosis (PBC) is an autoimmune disease, characterized by chronic biliary duct destruction, which mainly affects women aged between 35 and 45 years. Prolonged liver inflammation can cause scarring, leading to cirrhosis. The most common first clinical manifestations are pruritus, asthenia or jaundice, but most patients remain asymptomatic. PBC can be associated by itself with arthralgia, but polyarthritis and synovitis are exceptional. PBC is often associated with other non-hepatic autoimmune diseases, especially primary Sjogren's syndrome, which may favour articular involvement. PBC and rheumatoid arthritis (RA) have been suggested to coexist in 1.8 to 5.6% of patients with PBC, but data supporting this association are scarce. We report two cases of such an association. Both of these patients presented severe erosive RA. We discuss the therapeutic management of these patients, taking into account hepatic involvement and drug toxicity.

Assous N, Touzé E, Meune C, Kahan A, Allanore Y. · Rheumatology A Department, School of Medicine, René Descartes University, Cochin Teaching Hospital, Paris, France. · Joint Bone Spine. · Pubmed #17174586 No free full text.

Abstract: INTRODUCTION: Rheumatoid arthritis (RA) was independently associated with cardiovascular events in several studies, most of which were conducted in the US. OBJECTIVES: To estimate the risk of cardiovascular events in a cohort of RA patients recruited at a hospital in France, to identify cardiovascular risk factors, and to measure the severity of cardiovascular events. METHODS: Two hundred and thirty-nine patients admitted between January 1, 1998, and March 31, 1999, for RA meeting American College of Rheumatology criteria, with a negative history for cardiovascular events, were sent a questionnaire in 2004 to evaluate the occurrence of myocardial infarction, stroke, or cardiovascular death. RESULTS: During the mean follow-up of 5.4+/-1.8 years, there were 10 cases of myocardial infarction (0.8%/year), 3 cases of stroke (0.2%/year), and 9 cardiovascular deaths (0.7%/year). Of the 10 patients who experienced myocardial infarction, 5 had clinical symptoms of heart failure and 4 died from cardiovascular causes. Independent risk factors for cardiovascular events were older age (relative risk [RR], 2.5/10 years; 95% confidence interval [95%CI], 1.4-4.2), male gender (RR, 5.1; 95%CI, 1.8-14.6), treated hypertension (RR, 4.3; 95%CI, 1.4-13.2), and treated hypercholesterolemia (RR, 6.0; 95%CI, 1.8-20.7). CONCLUSION: Our data suggest a higher risk of cardiovascular events in patients with RA compared to the general population in France (0.1-0.5%/year for myocardial infarction and 0.07%/year for stroke in the age group covered by our cohort). Cardiovascular events in the patients with RA seemed unusually severe. Patients with RA should be carefully screened for conventional cardiovascular risk factors.

Avouac J, Sordet C, Depinay C, Ardizonne M, Vacher-Lavenu MC, Sibilia J, Kahan A, Allanore Y. · René Descartes University, Medical Faculty, Hôpital Cochin, France. · Arthritis Rheum. · Pubmed #16802363 links to  free full text

Abstract: OBJECTIVE: To determine the prevalence of sicca symptoms and Sjögren's syndrome (SS) in a 2-center prospective series of patients with systemic sclerosis (SSc), using the American-European Consensus Group criteria for SS. METHODS: Consecutive SSc patients hospitalized for followup care were evaluated for sicca symptoms. When the initial clinical evaluation yielded positive findings, a labial salivary gland biopsy was performed; histologic analysis evaluated focal lymphocytic sialadenitis and/or glandular fibrosis. Computed tomography and respiratory function tests were used to assess pulmonary fibrosis. RESULTS: We included 133 SSc patients (mean +/- SD age 55 +/- 13 years; mean +/- SD disease duration 6.5 +/- 6 years). Eighty-one patients had limited cutaneous SSc (lcSSc). Ninety-one patients (68%) had sicca syndrome. Histologic analysis revealed fibrotic involvement in 50 of these 91 patients, but labial salivary gland fibrosis was not associated with any organ involvement we evaluated. Nineteen of the 133 patients (14%) had SS. In this subgroup, lcSSc was present at a significantly higher frequency (18 of 19 patients) than in the remaining patients with sicca syndrome (39 of 72 patients) and the patients without sicca syndrome (24 of 42 patients). This subgroup also had a significantly higher frequency of anticentromere antibodies (18 of 19 patients) than did the remaining patients with sicca syndrome (19 of 72 patients) and the patients without sicca syndrome (5 of 42 patients). In addition, this subgroup had a significantly lower prevalence of pulmonary fibrosis (2 of 19 patients) than did the remaining patients with sicca syndrome (29 of 72 patients) and the patients without sicca syndrome (19 of 42 patients). CONCLUSION: There was a 68% prevalence of sicca syndrome in this prospective series of SSc patients. Sicca syndrome was related primarily to glandular fibrosis, the hallmark of SSc. The prevalence of secondary SS, as defined by the American-European Consensus Group criteria, was 14% and was markedly associated with lcSSc. We believe that lcSSc should be regarded as a specific autoimmune subgroup of SSc.

Lemarechal H, Allanore Y, Chenevier-Gobeaux C, Kahan A, Ekindjian OG, Borderie D. · Department of Biochemistry A, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, 75014 Paris, France. · Clin Chim Acta. · Pubmed #16716286 No free full text.

Abstract: OBJECTIVE: To examine protein oxidation in rheumatoid arthritis (RA) and evaluate its evolution after infliximab therapy in a subgroup of patients. METHODS: Seventy-one consecutive patients with RA were included. Among them, 30 patients refractory to conventional therapy were treated with infliximab. Serum markers of oxidative stress were determined at baseline and before the infusions of infliximab at weeks 6 and 30. Baseline values were compared with those in 30 healthy volunteers. RESULTS: Mean levels of serum carbonyl groups were significantly higher in RA patients than in controls (1.29+/-0.76 versus 0.58+/-0.39 nmol/mg of protein, p<0.0001), whereas thiol levels were found to be lower (238.3+/-61.6 versus 316.5+/-54.8 micromol/L, p<0.0001). Thiol levels inversely correlated with the disease activity score (r=-0.42, p=0.004), and with CRP values (r=-0.45, p=0.001). Immunoblots showed that albumin and heavy chain immunoglobulin were oxidized more markedly than in healthy volunteers. Significantly lower levels of thiol groups were detected in patients with refractory RA disease (208.9+/-66.8 versus 264.2+/-43.0 micromol/L, p<0.0004) but concentrations of carbonyl groups were similar. Short-term treatment with infliximab significantly decreased carbonyl groups (0.97+/-0.47 nmol/mg protein, p=0.02) and increased thiol (231.2+/-48.7 micromol/L, p=0.02) levels. CONCLUSION: Our results highlight free radical protein damage in RA and a link with inflammation, as underlined by the beneficial effects of infliximab.

Wipff J, Allanore Y, Kahan A, Meyer O, Mouthon L, Guillevin L, Pierlot C, Glikmans E, Bardin T, Boileau C, Cornélis F, Dieudé P. · Rheumatology A Department, Cochin Hospital, Paris, France. · Ann Rheum Dis. · Pubmed #16464986 No free full text.

Abstract: The minor allele of the R620W missense single-nucleotide polymorphism (SNP; rs2476601) in the PTPN22 (protein tyrosine phosphatase non-receptor 22) gene has been reported to be associated with multiple autoimmune diseases, including type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, juvenile idiopathic arthritis, autoimmune thyroiditis and vitiligo. Systemic sclerosis (SSc) is a connective tissue disease with some autoimmune abnormalities. The aim of our study was to test for association of the PTPN22*620W allele with SSc in a French Caucasian cohort with a case-control study of 121 patients with SSc and 103 controls. All patients and controls were genotyped for the PTPN22*R620W SNP. No association was found between the PTPN22*620W allele and SSc (7% v 9.2%, p = 0.39). The frequency of genotypes carrying at least one 620W allele was similar in both groups (13% v 17%, p = 0.38). The PTPN22*620W allele was also not associated with autoantibody patterns. Thus, the PTPN22*R620W polymorphism cannot be regarded as a genetic susceptibility factor for SSc in the French Caucasian population.

Lemarechal H, Allanore Y, Chenevier-Gobeaux C, Ekindjian OG, Kahan A, Borderie D. · Department of Biochemistry A, Paris 5 University, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris, France. · Clin Chim Acta. · Pubmed #16458876 No free full text.

Abstract: BACKGROUND: Thioredoxin (Trx)/thioredoxin reductase (TrxR) is a redox-active system induced by oxidative stress. We investigated its status as a function of RA disease activity. METHODS: 64 consecutive RA patients and 27 healthy subjects were enrolled in the study. Serum Trx protein levels were evaluated using an immunoassay and immunoblot, while redox Trx and TrxR activities and oxidative stress markers (carbonyl groups, thiols), were determined using spectrophotometric methods. RESULTS: Redox Trx activity and Trx protein concentrations were significantly higher in RA patients than in controls (redox Trx activity: 37.7+/-22.6 versus 21.1+/-7.9 ng/mL, p<0.01; Trx protein: 25.5+/-12.0 versus 12.3+/-5.1 ng/mL, p<0.0001). Redox Trx activity correlated with the DAS score (r=0.45, p=0.004) and with the tender joint count (r=0.49, p=0.002) whereas there was no correlation with Trx protein concentrations. Immunoblot analysis showed that circulating Trx was partially aggregated. TrxR activity was lower in the serum of RA patients than in healthy subjects (197+/-70 versus 263+/-56 U/L, p=0.002). TrxR activity was correlated with the DAS score (r=0.53, p<0.001) and with the tender joint count (r=0.36, p<0.01). There were no correlations between oxidative stress marker levels and redox Trx activity, Trx protein concentrations or TrxR activity. CONCLUSION: Redox Trx and TrxR activities correlated with the disease activity of RA patients consistent with the hypothesis that Trx/TrxR activities may contribute to disease activity in RA.

Avouac J, Guerini H, Wipff J, Assous N, Chevrot A, Kahan A, Allanore Y. · Service de rhumatologie A, Hôpital Cochin, 27 rue du faubourg Saint Jacques, 75014 Paris, France. · Ann Rheum Dis. · Pubmed #16414976 links to  free full text

Abstract: BACKGROUND: The osteoarticular and soft tissue structures of the hand may be involved in systemic sclerosis (SSc), causing functional disability. OBJECTIVE: To assess radiological hand features in a cross sectional study of SSc patients and in controls. METHODS: Hand radiology was done systematically in patients with SSc seen over a two year period and in unselected controls with rheumatoid arthritis or digital trauma. Two independent investigators blind to the diagnosis carried out the radiological assessment. RESULTS: 120 consecutive SSc patients (median (range) age, 56.5 (20 to 90) years; disease duration, 6 (0 to 42) years) and 42 controls (22 with rheumatoid arthritis and 20 with digital trauma) were studied. Radiological abnormalities in SSc patients included erosion (21%), joint space narrowing (28%), arthritis (defined by concomitant erosion and joint space narrowing) (18%), radiological demineralisation (23%), acro-osteolysis (22%), flexion contracture (27%), and calcinosis (23%). In univariate and multivariate analysis, the resorption of distal phalanges was significantly associated with digital ulcers, extra-articular calcification, and pulmonary arterial hypertension; flexion contracture was associated with the diffuse cutaneous form and high HAQ (Health Assessment Questionnaire) disability score. Calcinosis was most often seen in patients with digital ulcers, but was similarly observed in patients with the diffuse or limited cutaneous subtypes. CONCLUSIONS: Flexion contracture was associated with disability and occurred in patients with the diffuse cutaneous subtype of SSc, consistent with the tendency towards fibrosis and functional impairment of this subtype. Calcinosis and acro-osteolysis were both associated with vascular complications, highlighting a potential role of vascular injury in such lesions.

Allanore Y, Kahan A, Sellam J, Ekindjian OG, Borderie D. · Department of Rheumatology A, Assistance Publique-Hôpitaux de Paris, Cochin Hospital, Paris 5 University, 75679 Paris Cedex 14, France. · Clin Chim Acta. · Pubmed #16176811 No free full text.

Abstract: BACKGROUND: Patients with rheumatoid arthritis (RA) frequently display an atherogenic lipid profile which has been linked with inflammation. Tumor necrosis factor-alpha (TNF-alpha), a pivotal pro-inflammatory cytokine in RA may be involved in the development of the disturbed lipid metabolism. We investigated whether infliximab, an anti-TNF-alpha therapy, may modify the lipid profile. METHODS: 56 consecutive RA patients were treated with infliximab (3 mg/kg at weeks 0, 2, 6, 14, 22, 30). Lipid profile and CRP were assayed at baseline and before infusion at weeks 6 and 30. Baseline values were compared with those in 56 healthy volunteers. RESULTS: At baseline, the concentrations of HDL-cholesterol were lower in RA patients than in the controls (1.3+/-0.4 vs. 1.5+/-0.2 mmol/L; p<0.01). The triglyceride concentrations (1.6+/-0.8 vs. 1.3+/-0.4 mmol/L, p<0.01), the ratio of total cholesterol/HDL-cholesterol (4.3+/-1.6 vs. 3.2+/-0.5, p<0.001) and LDL-cholesterol/HDL-cholesterol (2.6+/-1.2 vs. 1.7+/-0.5, p<0.001) were significantly higher in RA patients than in controls. After 6 weeks of infliximab therapy, the mean total cholesterol concentration increased by 25% (p<0.001), LDL-cholesterol by 24% (p<0.001) and HDL-cholesterol by 30% (p<0.001). The decrease in CRP levels to 30 week inversely correlated with the increase in HDL-cholesterol (r=-0.47, p=0.005). CONCLUSIONS: Infliximab administration is associated with important increases in cholesterol levels in all its forms but as no significant beneficial effect on the atherogenic ratio.

Assous N, Allanore Y, Batteux F, Meune C, Toulon P, Weill B, Kahan A. · Department of Rheumatology A, Paris 5 University, Assistance Publique Hôpitaux de Paris, Cochin Hospital, Paris, France. · Clin Exp Rheumatol. · Pubmed #15895890 No free full text.

Abstract: OBJECTIVE: To investigate the prevalence and clinical significance of antiphospholipid antibodies in patients with systemic sclerosis (SSc). METHODS: Autoantibodies against cardiolipin (aCL) and beta2-glycoprotein 1 (beta2-GPI) were detected by enzyme-linked immunoabsorbent assays (ELISAs) in successively hospitalised SSc patients admitted during a 24-month period. These patients were compared to patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA). RESULTS: 108 SSc patients were included: 61 had limited cutaneous SSc, 47 had the diffuse sub-type, 16 had primitive pulmonary arterial hypertension (PAH) and 34 had digital ulcerations. The control groups consisted of 37 RA and 38 SLE patients. The prevalence of aCL positivity was lower in SSc patients vs SLE patients (14 vs 47%; p < 0.001), lower in RA patients vs SLE patients (19 vs 47%; p < 0.001), and not different in SSc vs RA patients (14 vs 19%; NS). The mean aCL titer was also lower in SSc vs SLE patients (8+/-10 vs 15+/-20; p < 0.001). In SSc patients, positivity for aCL was associated with PAH (p = 0.009) and the aCL titer correlated with that of the von Willebrand antigen factor (r= 0.23; p = 0.045). The prevalence of anti beta2-GPI positive patients (IgG and/or IgM) was 5% in the SSc group, 18% in the SLE group and 5% in the RA group (SLE vs SSc and SLE vs RA; p = 0.005). CONCLUSION: We found that the prevalence of antiphospholipid antibodies in SSc patients was low. However, aCL antibodies were associated with PAH and endothelial injury.

Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, Larroche C, Soubrier M, Bouillet L, Dougados M, Fain O, Farge D, Kyndt X, Lortholary O, Masson C, Moura B, Remy P, Thomas T, Wendling D, Anaya JM, Sibilia J, Mariette X, Anonymous00301. · Service de Rhumatologie, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France. · Ann Rheum Dis. · Pubmed #15550531 links to  free full text

Abstract: OBJECTIVE: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice. METHODS: 866 rheumatology and internal medicine practitioners were contacted by e-mail to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated. RESULTS: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjogren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease. CONCLUSIONS: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis.

Allanore Y, Borderie D, Hilliquin P, Hernvann A, Levacher M, Lemaréchal H, Ekindjian OG, Kahan A. · Department of Rheumatology A, Cochin Hospital, René Descartes University, Paris 75014, France. · Rheumatology (Oxford). · Pubmed #11600736 links to  free full text

Abstract: OBJECTIVE: To investigate nitric oxide (NO) production and inducible NO synthase expression by cultured peripheral blood mononuclear cells (PBMC) in patients with systemic sclerosis (SSc). METHODS: Eighteen patients with SSc were compared with two control groups: 16 patients with rheumatoid arthritis (RA) and 23 patients with mechanical sciatica. Nitrate was determined by fluorimetry in plasma and by spectrophotometry in supernatants. Inducible NO synthase (iNOS) was detected in cultured PBMC by immunofluorescence, immunoblotting and flow cytometry with or without treatment of the cells with interleukin (IL) 1beta+ tumour necrosis factor alpha (TNF-alpha), IL-4 or interferon gamma (IFN-gamma) from day 1 to day 5. RESULTS: NO metabolite concentrations were lower in SSc patients (mean+/-s.e.m. 34.3+/-2.63 micromol/l) than in RA (48.3+/-2.82 micromol/l; P<0.02) and sciatica (43.3+/-5.24 micromol/l; P<0.03) patients. iNOS was detected in cultured monocytes in all three groups but induction occurred on day 1 in RA, day 2 in sciatica and only on day 3 in SSc, whatever the stimulus. CONCLUSIONS: The concentrations of NO metabolites are decreased in SSc patients and the metabolism of these compounds in PBMC is altered. Low levels of NO, a vasodilator, may be involved in vasospasm, which is critical in SSc. This may have therapeutic implications.

Menkès CJ, Allanore Y, Borderie D, Hilliquin P, Hernvann A, Ekindjian O, Kahan A. · Service de Rhumatologie A, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques-75679 Paris. · Bull Acad Natl Med. · Pubmed #11501260 No free full text.

Abstract: We investigated nitric oxide (NO) production and inducible NO synthase (iNOS) expression by cultured peripheral blood mononuclear cells (PBMC) in systemic sclerosis (SSc). Eighteen patients with SSc were compared to two control groups: 16 rheumatoid arthritis patients (RA) and 23 mechanical sciatica patients. The sum of nitrites and nitrates was determined by fluorimetry in sera and spectrophotometry in supernatants. Inducible iNOS was detected in cultured PBMC by immunofluorescence, immunoblot and flow cytometry with or without IL-1 beta + TNF alpha, IL-4 or IFN gamma from day 1 to day 5. NO metabolite concentrations in the plasma were lower in SSc (34.3 mumol/l +/- 2.63 SEM) than in RA (48.3 mumol/l +/- 2.2; p < 0.02) and sciatica (43.3 mumol/l +/- 5.24; p < 0.03) patients. iNOS was detected in cultured monocytes in the 3 groups but induction occurred on day 1 in RA, day 2 in sciatica and only on day 3 in SSc, whatever the stimulus. The concentrations of NO metabolites are decreased in SSc patients and the induction of iNOS in PBMC is delayed. Low levels of NO, a vasodilator, may be involved in vasospasm, which is critical in SSc. This may suggest therapeutic implications.

Allanore Y, Le Gars L, Duron F, Christin-Maître S, Kaplan G, Berenbaum F. · Service de Rhumatologie, Hôpital Saint-Antoine, Paris. · Presse Med. · Pubmed #11109434 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis and insulin-dependent diabetes mellitus are both autoimmune disorders of unknown etiology. We report the case of a patient who developed the two diseases simultaneously. CASE REPORT: A 64-year-old man with no remarkable medical history developed insulin-dependent diabetes disclosed by ketoacidosis that occurred 3 weeks after onset of a bilateral symmetrical polyarthritic syndrome characteristic of rheumatoid arthritis. DISCUSSION: These two disorders share common susceptibility of subjects with MHC class II molecules HLA DRB1*04. Immunological studies have also shown a common Th1 type cytokine-secretion pattern in both diseases. Epidemiological studies have not however clearly demonstrated a link between them.

Hilliquin P, Allanore Y, Coste J, Renoux M, Kahan A, Menkès CJ. · Service de Rhumatologie A, Hôpital Cochin, Paris, France. · Rheumatology (Oxford). · Pubmed #10986309 links to  free full text

Abstract: OBJECTIVE: To determine the cumulative incidence and the point prevalence of atopy in patients with rheumatoid arthritis (RA). PATIENTS AND METHODS: A standardized questionnaire was sent to 300 RA patients. Questions concerned previous or present characteristics of atopy (hay fever, asthma and constitutive eczema) and RA. RA patients were matched with genetically unrelated controls (sister- or brother-in-law, neighbour or friend). The same questionnaire (except for questions about RA) was sent to the control subjects. In cases of atopy, patients, controls and the treating physicians were contacted by a physician to check the validity of the responses. RESULTS: Paired responses were obtained in 173 cases. Information about atopy was obtained for 69 other RA patients. The characteristics of RA were similar for patients who responded and those who did not respond. The frequency of atopy was significantly lower in RA patients than in controls, both for cumulative incidence (RA 7.5%, controls 18.8%; P: < 0.01) and point prevalence (RA 3.5%, controls 16.2%; P: < 0.0001). The clinical manifestations of atopy stopped before the onset of RA in eight of the 17 RA patients with an allergic condition, and there was no subsequent relapse. No effect of RA treatment could account for the remission of atopy. CONCLUSION: These data support the concept that atopy protects against the future development of RA and that the two diseases could counterbalance one another.

Claudepierre P, Allanore Y, Belec L, Larget-Piet B, Zardi L, Chevalier X. · Department of Rheumatology, Hôpital Henri Mondor, 94010 Créteil, Paris, France. · Rheumatology (Oxford). · Pubmed #10556262 links to  free full text

Abstract: OBJECTIVE: To determine, for the first time, plasma levels of general fibronectin (Fn) and two spliced isoforms, Ed-A and Ed-B, in patients with spondyloarthropathy (SpA) in comparison with rheumatoid arthritis (RA) patients and healthy volunteers (HV). METHODS: Plasmas (EDTA) as well as clinical data, erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were collected in two groups of 10 patients fulfilling the European Spondylarthropathy Study Group criteria for SpA or the 1987 American College of Rheumatology criteria for RA. Plasmas of 21 blood donors served as controls. Plasma levels of Fns were determined by using an in-house immunocapture ELISA, using monoclonal antibodies (MAbs) against general Fn and its isoforms. RESULTS: Total Fn plasma levels were significantly higher in the SpA group (mean+/-S.D.=1387+/-569 mg/l) than in the RA group (684+/-196 mg/l; P=0.02) and in HV (303+/-211 mg/l; P<0.0001). Ed-A Fn levels appeared higher in SpA (23+/-10.4 mg/l) and RA (32.5+/-16.5 mg/l) groups than in the HV group (2.8+/-0.9 mg/l; P=0.0003 and P<0.0001, respectively), without a significant difference between SpA and RA groups. Ed-B Fn levels were higher in SpA (6.9+/-2.1 mg/l) than in RA (3.2+/-1.9 mg/l; P=0. 02) and HV (1.1+/-0.8 mg/l; P=0.0003) groups. No significant correlation was observed in SpA patients between each Fn level and clinical activity, ESR or CRP levels. CONCLUSIONS: This study showed an increase in plasma levels of Fn and Ed-B Fn in SpA patients compared with RA patients and HV, which could not be attributed solely to systemic inflammation. It may be hypothesized that Ed-A and Ed-B Fn might reflect local turnover in inflamed tissues, and that Ed-B Fn might be particularly involved in the musculoskeletal inflammatory process of SpA.