Rheumatoid Arthritis: Cantagrel A

El Mahou S, Popa L, Constantin A, Cantagrel A, Aberrane A, Jamard B, Mazieres B, Laroche M. · Hôpital de Rangueil, 1, 1 avenue Poulhes, 31059, Toulouse, France. · Clin Rheumatol. · Pubmed #16565898 No free full text.

Abstract: Remitting seronegative symmetrical synovitis pitting oedema (RS3PE) is a distinct form of seronegative rheumatoid arthritis like polyarthritis. It is characterized by late onset symmetrical joint involvement and pitting oedema of hands and feet (JAMA 254(19):2763-2767, [1]). Polyarthritis secondary to intravesical Bacillus Calmette Guerin (BCG) therapy has been reported (Clin Rheumatol 21:536-537, [2]). To our knowledge, about 0.5% of patients receiving BCG instillation presented polyarthritis, but only one case of RS3PE has been reported (J Rheumatol 28:1699-1701, [3]). We described the second case of RS3PE following intravesical BCG instillation of bladder carcinoma.

Meyer O, Nicaise-Roland P, Santos MD, Labarre C, Dougados M, Goupille P, Cantagrel A, Sibilia J, Combe B. · Rheumatology Unit, Assistance Publique Hôpitaux de Paris, Bichat University Hospital, 75018 Paris, France. · Arthritis Res Ther. · Pubmed #16469118 links to  free full text

Abstract: The objective of this study was to evaluate the potential of serially determined anti-cyclic citrullinated peptide (CCP) antibodies for predicting structural joint damage in patients with early rheumatoid arthritis (RA), compared to a single baseline determination. Ninety-nine RA patients with disease durations of less than one year and no history of disease-modifying antirheumatic drug therapy were followed prospectively for at least five years. Anti-CCP2 concentrations were measured using a second-generation ELISA. Sharp scores as modified by van der Heijde were determined on hand and foot radiographs. Anti-CCP2 antibodies were detected in 55.5% of patients at baseline and 63.6% at any time during the first three years. Presence of anti-CCP2 at any time during the first three years was associated with radiographic damage at baseline (odds ratio (OR), 3.66; 95% confidence interval (95% CI) 0.99-13.54) and with five year progression of the total Sharp score (OR, 3.17; 95% CI, 1.3-7.7), erosion score (OR, 5.3; 95% CI, 1.4-19.2) and joint space narrowing score (OR, 2.8; 95% CI, 1.15-6.8). The presence of anti-CCP2 or IgM RF at baseline did not predict these outcomes. Patients with negative anti-CCP2 tests throughout follow-up had less radiographic progression than patients with increasing anti-CCP2 concentrations; they did not differ from patients with decreasing anti-CCP2 antibody levels. HLADRB1* typing showed that progression of the mean modified Sharp score was not correlated with the presence of the shared epitope alleles. In conclusion, serially determined anti-CCP2 antibodies during the first three years of follow-up performs better than baseline determination for predicting radiographic progression in patients with early RA.

Gourraud PA, Boyer JF, Barnetche T, Abbal M, Cambon-Thomsen A, Cantagrel A, Constantin A. · INSERM U558, Toulouse, France. · Arthritis Rheum. · Pubmed #16447236 links to  free full text

Abstract: OBJECTIVE: A new classification of HLA-DRB1 alleles supporting the shared epitope hypothesis of rheumatoid arthritis (RA) susceptibility was recently introduced. We investigated the relevance of this classification in terms of the structural severity of RA. METHODS: The study group comprised 144 patients who were included in a prospective longitudinal cohort of French Caucasoid patients with early RA. Progression of the total radiographic damage score (Sharp/van der Heijde method) was used to quantify the structural severity of RA after 4 years of followup. HLA-DRB1 typing and subtyping were performed by polymerase chain reaction, using a panel of sequence-specific oligonucleotide probes. HLA-DRB1 alleles were classified according to the above-mentioned new system. The association between the HLA-DRB1 allele groups (S1, S2, S3P, S3D, and X) and the structural severity of RA was analyzed with nonparametric statistical tests. RESULTS: The presence of S2 alleles (HLA-DRB1*0401 and HLA-DRB1*1303) was associated with severe forms of RA (P = 0.004); a significant dose effect was observed (P = 0.01). The presence of S3D alleles (HLA-DRB1*11001, HLA-DRB1*1104, HLA-DRB1*12, and HLA-DRB1*16) was associated with benign forms of RA (P < 0.0001), and a significant dose effect was observed (P < 0.01). CONCLUSION: The studied classification of HLA-DRB1 alleles is relevant in terms of RA outcomes. Compared with a previously described classification system, this system differentiates predisposing (S2) and protective (S3D) alleles for RA structural severity, which, respectively, correspond to KRRAA and DRRAA amino acid patterns at position 70-74 of the third hypervariable region of the HLA-DRbeta chain.

Auger I, Sebbag M, Vincent C, Balandraud N, Guis S, Nogueira L, Svensson B, Cantagrel A, Serre G, Roudier J. · INSERM UMR 639, La Conception Hospital, Faculté de Médecine, 27 Boulevard Jean Moulin, 13005 Marseille, France. · Arthritis Rheum. · Pubmed #16255019 links to  free full text

Abstract: OBJECTIVE: Antibodies directed against citrullinated fibrinogen are highly specific for rheumatoid arthritis (RA). This study was undertaken to test whether RA-associated HLA-DR alleles are associated with anti-citrullinated fibrinogen in RA patient sera and whether replacement of arginyl by citrullyl residues on fibrinogen peptides modifies their binding to HLA-DR molecules and their recognition by T cells. METHODS: Antikeratin, antifilaggrin, and anti-citrullinated fibrinogen antibodies were assayed in RA patients who had undergone HLA-DR typing. Direct assays were performed to investigate binding of citrullinated or native fibrinogen peptides (encompassing the entire alpha- and beta-chains of fibrinogen) to purified HLA-DR molecules. T cell proliferative responses to citrullinated or native fibrinogen peptides were measured in RA patients and controls. RESULTS: HLA-DRB1*0404 was associated with anti-citrullinated fibrinogen in RA sera (P = 0.002). For the RA-associated alleles HLA-DRB1*0401 and HLA-DR1, there was a nonsignificant trend toward association (P = 0.07). Multiple peptides from the alpha- and beta-chains of fibrinogen bound many HLA-DR alleles; DRB1*0404 was the best fibrinogen peptide binder. Citrullination did not influence fibrinogen peptide binding to HLA-DR or fibrinogen peptide recognition by T cells. Peripheral blood T cells that recognized native or citrullinated fibrinogen peptides were common in RA patients but not in healthy controls. CONCLUSION: The RA-associated HLA-DRB1*0404 allele is also associated with production of antibodies to citrullinated fibrinogen. DRB1*0401 and DRB1*01 tend to be associated with anti-citrullinated fibrinogen, but this is not statistically significant. Citrullination of fibrinogen peptide does not influence peptide-DR-T cell interaction. Finally, T cell proliferation in response to citrullinated or uncitrullinated fibrinogen peptides is frequent in RA patients and very infrequent in controls.

Le Loët X, Berthelot JM, Cantagrel A, Combe B, De Bandt M, Fautrel B, Flipo RM, Lioté F, Maillefert JF, Meyer O, Saraux A, Wendling D, Guillemin F. · Department of Rheumatology, Rouen University Hospital, France. · Ann Rheum Dis. · Pubmed #15994280 links to  free full text

Abstract: OBJECTIVE: To elaborate a clinical practice decision tree for the choice of the first disease modifying antirheumatic drug (DMARD) for untreated rheumatoid arthritis of less than six months' duration. METHODS: Four steps were employed: (1) review of published reports on DMARD efficacy against rheumatoid arthritis; (2) inventory of the information available to guide DMARD choice; (3) selection of the most pertinent information by 12 experts using a Delphi method; and (4) choice of DMARDs in 12 clinical situations defined by items selected in step 3 (28 joint disease activity score (DAS 28): < or =3.2; >3.2 and < or =5.1; >5.1; rheumatoid factor status (positive/negative); structural damage (with/without)-that is, 3 x 2 x 2). Thus, multiplied by all the possible treatment pairs, 180 scenarios were obtained and presented to 36 experts, who ranked treatment choices according to the Thurstone pairwise method. RESULTS: Among the 77 items identified, 41 were selected as pertinent to guide the DMARD choice. They were reorganised into five domains: rheumatoid arthritis activity, factors predictive of structural damage; patient characteristics; DMARD characteristics; physician characteristics. In the majority of situations, the two top ranking DMARD choices were methotrexate and leflunomide. Etanercept was an alternative for these agents when high disease activity was associated with poor structural prognosis and rheumatoid factor positivity. CONCLUSIONS: Starting with simple scenarios and using the pairwise method, a clinical decision tree could be devised for the choice of the first DMARD to treat very early rheumatoid arthritis.

Middleton J, Americh L, Gayon R, Julien D, Mansat M, Mansat P, Anract P, Cantagrel A, Cattan P, Reimund JM, Aguilar L, Amalric F, Girard JP. · Endocube S.A.S., Prologue Biotech-BP-700, Rue Pierre et Marie Curie, 31319 Labege Cedex, France. · J Pathol. · Pubmed #15887283 No free full text.

Abstract: Endothelial cells play a central role in chronic inflammation: for example, they express adhesion molecules and present chemokines leading to enhanced leukocyte recruitment into tissues. Numerous markers of endothelial cells have been reported but there has been a lack of comparative data on their specificity. The present study compared the specificity of seven endothelial cell markers in the rheumatoid synovium and the colon of patients with Crohn's disease. These markers were: the sulphated epitope MECA-79, the Duffy antigen receptor for chemokines (DARC), von Willebrand factor, CD31 (PECAM-1), CD34, CD105 (endoglin) and CD146. MECA-79, DARC and von Willebrand factor showed a specific endothelial cell distribution. MECA-79, which recognizes sulphated ligands for leukocyte adhesion receptor L-selectin (CD62L), was selective for a subset of venules in highly inflamed tissue and was present in rheumatoid but not control osteoarthritic synovia. DARC was also specific for venules but had a more widespread distribution than MECA-79, and was present in rheumatoid and control synovia. The other markers all labelled endothelial cells in venules, arterioles and capillaries. However, they also localized to other cell types. For example, CD34 stained fibroblasts, CD146 was expressed by the pericytes and smooth muscle cells of vessel walls and CD31 and CD105 labelled a broad range of cell types.

Saraux A, Guillemin F, Guggenbuhl P, Roux CH, Fardellone P, Le Bihan E, Cantagrel A, Chary-Valckenaere I, Euller-Ziegler L, Flipo RM, Juvin R, Behier JM, Fautrel B, Masson C, Coste J. · Rheumatology Unit, University Hospital, Brest-Cedex, France. · Ann Rheum Dis. · Pubmed #15817661 links to  free full text

Abstract: OBJECTIVE: To estimate the prevalence of spondyloarthropathies (SpAs) in France in a multiregional representative sample in the year 2001. METHODS: A two stage random sample was constituted in seven areas from the national telephone directory and the next birthday method in each household. Interviewers were patient-members of self help groups trained to administer telephone surveys using a validated questionnaire for detecting inflammatory joint disease. Quality of data collection was controlled periodically. SpA was confirmed by the patient's rheumatologist or by clinical examination. Prevalence estimates after probability sampling correction were standardised for age and sex (1999 national census). RESULTS: Among the 15 219 anonymous telephone numbers selected, 3.6% were places of work or secondary residences and were excluded. The phone interview participation rate ranged across regions from 55.1 to 69.9%. 3554 men and 5841 women were included in the study. Twenty nine cases of SpA were confirmed. All but one fulfilled ESSG criteria. Mean age was 47 years (range 21-78). The overall prevalence standardised for age and sex was 0.30% (95% confidence interval (CI) 0.17 to 0.46). Prevalence was similar in women (0.29% (95% CI 0.14 to 0.49)) and men (0.31 % (95% CI 0.12 to 0.60)). Geographical analysis by department clustering found no significant differences. The prevalence of SpA was as high as that of rheumatoid arthritis. CONCLUSION: Prevalence of SpA in France was 0.30% in 2001, with no difference between women and men. Ankylosing spondylitis and psoriatic arthritis were the most common SpA subsets.

Guillemin F, Saraux A, Guggenbuhl P, Roux CH, Fardellone P, Le Bihan E, Cantagrel A, Chary-Valckenaere I, Euller-Ziegler L, Flipo RM, Juvin R, Behier JM, Fautrel B, Masson C, Coste J. · EA 3444 School of Public Health, Faculty of Medicine, University of Nancy, Nancy, France. · Ann Rheum Dis. · Pubmed #15800010 links to  free full text

Abstract: BACKGROUND: Prevalence estimates of rheumatoid arthritis (RA) vary across Europe. Recent estimates in southern European countries showed a lower prevalence than in northern countries. OBJECTIVES: To estimate the prevalence of RA in France in a multiregional representative sample in the year 2001. METHODS: A two stage random sample was constituted in seven areas (20 counties) from the national telephone directory of households and by the next birthday method in each household. Patient-interviewers, member of self help groups, were trained to administer telephone surveys using a validated questionnaire for case detection of inflammatory rheumatism, and conducted the survey under quality control. All suspected cases of RA were confirmed by their rheumatologist or by clinical examination. Prevalence estimates after probability sampling correction were standardised for age and sex (national census 1999). RESULTS: An average response rate of 64.7% (two stages combined) led to a total of 9395 respondents. Standardised prevalence was 0.31% (95% confidence interval 0.18 to 0.48) for RA, 0.51% in women and 0.09% in men, with a higher age-specific prevalence in the 65-74 year age band. A geographical analysis of county clustering showed significant variation across the country. CONCLUSION: This national multiregional cooperative study demonstrates the usefulness of working in association with patients of self help groups. It showed a similar prevalence of RA to that of the spondyloarthropathies estimated concomitantly during the survey. It provides a reliable basis for definition of population targets for healthcare delivery and drug treatments.

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.

Gossec L, Dougados M, Goupille P, Cantagrel A, Sibilia J, Meyer O, Sany J, Daurès JP, Combe B. · René Descartes University, Cochin Hospital, Department of Rheumatology B, Paris, France. · Ann Rheum Dis. · Pubmed #15140774 links to  free full text

Abstract: OBJECTIVE: To determine prognostic factors for remission in early rheumatoid arthritis. METHODS: 191 patients with rheumatoid arthritis whose disease duration was less than one year were followed up prospectively for five years. Remission, defined by a disease activity score (DAS) of <1.6, was used as the outcome measure. Baseline clinical, laboratory, genetic, and radiographic data (with radiographic scores determined by Sharp's method, modified by van der Heijde) were obtained. RESULTS: 48 patients (25.1%) fulfilled the remission criteria at the three year follow up visit, and 30 (15.7%) at three and five years. On univariate analysis by Fisher's exact test, remission at three years and persistent remission at five years were closely correlated with baseline DAS values, C reactive protein level, Ritchie score, health assessment questionnaire score, duration of morning stiffness, and to a lesser extent baseline total radiological scores and rheumatoid factor negativity. No significant correlation was found with sex, age, extra-articular manifestations, erythrocyte sedimentation rate, anti-cyclic citrullinated protein antibodies, anti-keratin antibodies, anti-HSP 90, anticalpastatin antibodies, antinuclear antibodies, or HLA-DRB1* genotypes. Logistic regression analysis showed that the baseline independent variables predictive of remission were low DAS, Ritchie score, morning stiffness duration, and total radiographic score. CONCLUSIONS: Baseline prognostic factors for remission in early rheumatoid arthritis were mainly clinical markers of disease activity and radiological scores.

Constantin A, Dieudé P, Lauwers-Cancès V, Jamard B, Mazières B, Cambon-Thomsen A, Cornélis F, Cantagrel A. · Centre Hospitalier Universitaire Rangueil, INSERM U558, and INSERM U563, Toulouse, France. · Arthritis Rheum. · Pubmed #15022314 links to  free full text

Abstract: OBJECTIVE: The gene encoding tumor necrosis factor receptor type II (TNFRII) is a strong candidate in the pathogenesis of rheumatoid arthritis (RA). An association between a single-nucleotide polymorphism (196M/R) in exon 6 of the TNFRII gene and familial RA was recently reported. The present study was undertaken to test the hypothesis that there is an association between this polymorphism and the severity of RA. METHODS: One hundred two white patients with early RA were included in this prospective study. The French version of the Health Assessment Questionnaire (F-HAQ) and a radiographic damage score (modified Sharp/van der Heijde method) were used to quantify the functional and structural severity of RA at baseline and after 4 years of followup. TNFRII 196M/R polymorphism genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: Among the 102 patients with RA, 63 (61.8%) were homozygous for the 196M allele, 36 (35.3%) were heterozygous for alleles 196M and 196R, and 3 (2.9%) were homozygous for the 196R allele. At baseline, the median radiographic and F-HAQ scores did not differ between RA patients who carried the 196R allele and those who did not. After 4 years of followup, the F-HAQ score was higher in RA patients carrying the 196R allele (median 1 [interquartile range (IQR) 0.125, 1.375]) than in noncarriers (0.375 [IQR 0, 1]) (P = 0.02), while the median radiographic score did not differ between RA patients who carried the 196R allele and those who did not. CONCLUSION: The results of the present study support the hypothesis that there is an association between the TNFRII 196 M/R gene polymorphism and the functional severity of early RA.

Saraux A, Guillemin F, Fardellone P, Guggenbuhl P, Behier JM, Cantagrel A, Euller-Ziegler L, Flipo RM, Juvin R, Le Loet X, Masson C, Sany J, Schaeverbeke T, Coste J, Anonymous00053. · Rheumatology Department, Hôpital de la Cavale Blanche, CHU Brest, 29609 Brest cedex, France. · Joint Bone Spine. · Pubmed #14769520 No free full text.

Abstract: OBJECTIVE: To evaluate agreement between a rheumatologist visit and a telephone interview by a patient organization member, regarding the diagnosis of rheumatoid arthritis (RA) or spondyloarthropathy (SpA) and the classification criteria for these two conditions. METHOD: Patients underwent a standardized interview and physical examination by hospital-based rheumatologists, who diagnosed RA in 230 cases, SpA in 175, and other conditions (controls) in 195. Members of patient organizations then used a standardized questionnaire to interview the patients by telephone about their diagnosis and about 1987 ACR classification criteria for RA and the ESSG criteria for SpA. RESULTS: Agreement between the two sources of data was poor for the classification criteria but satisfactory for the diagnosis (kappa, 0.84 (0.81-0.87) for RA and 0.78 (0.75-0.81) for SpA). CONCLUSION: Standardized telephone interviews conducted by patient organization members accurately identify the diagnosis made by rheumatologists based on a physical examination and medical record review, whereas agreement is poor regarding classification criteria for RA and SpA.

Combe B, Cantagrel A, Goupille P, Bozonnat MC, Sibilia J, Eliaou JF, Meyer O, Sany J, Dubois A, Daurès JP, Dougados M. · Service d'Immuno-Rhumatologie, CHU Montpellier, INSERM U454, 34295 Montpellier cedex 5, France. · J Rheumatol. · Pubmed #14677175 No free full text.

Abstract: OBJECTIVE: To determine prognostic factors of disability in early rheumatoid arthritis (RA) and to investigate the radiological and functional course of the disease. METHODS: A total of 191 patients with early RA (diagnosed for less than one year) according to American College of Rheumatology criteria were followed prospectively for 5 years. At baseline and at endpoint, Stanford Health Assessment Questionnaire (HAQ) scores and radiological scores (Sharp's score modified by van der Heijde) were performed. Correlations between numerous baseline data and HAQ score at endpoint were analyzed, using nonparametric tests. A multilinear regression model was performed to select independent prognostic factors of HAQ disability. RESULTS: During the 5-year followup, mean HAQ decreased from 1.3 (+/- 0.7) to 0.6 (+/- 0.6). There were 98 (65.3%) patients with a score > 1 point at baseline, but only 46 (27.4%) after 3 years and 34 (21.8%) after 5 years. Moreover, 90% of the patients had an improvement of the disability score. Final HAQ disability was associated with baseline values of HAQ score, Pain, Ritchie index, tender joint count, Disease Activity Score, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and erosion. Multivariate analysis selected baseline HAQ score, Ritchie index, ESR, CRP, and presence of erosion as independent prognostic factors of HAQ disability. The probability cutoff in the logistic model was selected to minimize the sum of false positive and false negative values: negative predictive value = 92.71%, positive predictive value = 46.15%, p = 0.408. Sex, age, IgM and IgA rheumatoid factors, other tested autoantibodies, and HLA class II genes did not contribute significantly to prediction of the disability after 5 years. At baseline, mean scores were 3.6 units (+/- 7.7) for total radiological score, 1.7 (+/- 4.5) for erosion score, and 1.9 (+/- 3.7) for joint space narrowing score. After 5 years, they were 17.9 +/- 22.3, 6.9 +/- 9.5, and 11.0 +/- 15.4, respectively. No erosion was present at the start in 58.0% of patients, compared to 24.2% and 22.4% at 3 and 5 years. Global radiographic progression concerned 87 patients (55.8%) during the 5 years. CONCLUSION: During the first 5 years of RA, radiological damage increased progressively in half of the patients, whereas HAQ disability improved in most of them during the same period of time and could be predicted by baseline values of HAQ score, Ritchie index, ESR, CRP, and presence (or absence) of erosion.

Maillefert JF, Combe B, Goupille P, Cantagrel A, Dougados M. · Centre Hospitalier Universitaire Dijon, Dijon, France. · Rheumatology (Oxford). · Pubmed #14623945 links to  free full text

Abstract: OBJECTIVE: To evaluate the predictive validity of radiological change on 5-yr disability in rheumatoid arthritis (RA). METHODS: The study was designed to be multicentre, prospective, longitudinal, with a 5-yr follow-up. Participants were RA patients (ACR criteria), with a disease duration of <1 yr at entry. Radiographs of the hands and feet in posteroanterior view at baseline and after 12 months of follow-up (van der Heijde's modification of Sharp method) were used for structural evaluation. Disability was evaluated with Health Assessment Questionnaire (HAQ) at yr 5. Analyses consisted of (i) correlation existing between the changes in the radiological scores during the first year and the HAQ value at yr 5 and (ii) determination of the optimal cut-off in the changes in the radiological scoring system, by ROC curve analysis, in which variable to be explained was disability status at yr 5, defined by HAQ value of at least 1. RESULTS: Due to missing data and/or lost to follow-up, 135 patients (out of the 191 recruited patients) were included in the analyses (mean change in the radiological score = 4.9 +/- 8.7 points, mean HAQ at yr 5 = 0.62 +/- 0.68). There was a statistically significant correlation between the HAQ-disability status at yr 5 and the changes observed in the radiological total damage and narrowing scores during the first year (r = 0.18, P = 0.046 and r = 0.25, P = 0.006, respectively). Conversely, the short-term changes in the erosion score were not correlated with subsequent HAQ-disability (r = 0.084, P = 0.36). A change of at least 2 points in the total X-ray score was considered as optimal (sensitivity, specificity, positive and negative predictive values of 66.7, 53.9, 32.8 and 82.8%, respectively). CONCLUSION: This work shows that early changes in joint damage in patients with recent-onset RA are related to subsequent HAQ-disability. This relationship is due to changes in narrowing, rather than in erosion score, suggesting that the joint narrowing score might be of great importance in the follow-up of RA patients and in the reports of scientific results. The weak performance of the thresholds established using predictive validity for subsequent HAQ-disability compromise their use at the individual level.

Meyer O, Labarre C, Dougados M, Goupille P, Cantagrel A, Dubois A, Nicaise-Roland P, Sibilia J, Combe B. · Service de Rhumatologie, CHU Bichat, AP-HP, Paris, France. · Ann Rheum Dis. · Pubmed #12525380 links to  free full text

Abstract: OBJECTIVE: To study the value of antibodies to citrullinated proteins/peptides for predicting joint outcomes in patients with recent onset rheumatoid arthritis (RA). METHODS: 191 patients with RA onset within the past year were followed up prospectively for five years. Serum samples obtained from 145 patients at baseline before disease modifying antirheumatic drug treatment were examined using three anticitrullinated protein/peptide antibody assays: antiperinuclear factor (APF) by indirect immunofluorescence (IIF), antikeratin antibodies (AKA) by IIF, and anti-cyclic citrullinated peptide (CCP) antibodies by enzyme linked immunosorbent assay (ELISA). Radiographs of the hands and feet taken at baseline and after three and five years were evaluated using Sharp scores modified by van der Heijde. RESULTS: Anti-CCP ELISA was positive in 58.9% of patients. APF/anti-CCP agreement was 77%. The likelihood of a total Sharp score increase after five years was significantly greater among patients with anti-CCP antibodies (67%; odds ratio (OR) 2.5; 95% confidence interval (95% CI) 1.2 to 5.0) or APF (57%; OR 2.4; 95% CI 1.2 to 4.9) but not rheumatoid factor (RF; OR 0.7; 95% CI 0.3 to 1.5). Mean values for radiographic damage, erosion, and joint narrowing scores at the three times were significantly higher in patients with anti-CCP or APF than in those without. AKA did not significantly predict radiographic damage. In separate analyses of patients with and without RF, anti-CCP or APF was better than RF for predicting total joint damage and joint damage progression after five years. CONCLUSION: Antibodies to citrullinated proteins/peptides determined early in the course of RA by APF IIF or anti-CCP ELISA are good predictors of radiographic joint damage. Further studies of clinical, laboratory, and genetic parameters are needed to improve RA outcome prediction in clinical practice.

Vincent C, Nogueira L, Sebbag M, Chapuy-Regaud S, Arnaud M, Letourneur O, Rolland D, Fournié B, Cantagrel A, Jolivet M, Serre G. · Institut National de la Santé et de la Recherche Médicale (CJF 96-02, IFR30), Purpan School of Medicine, University of Toulouse III, Toulouse, France. · Arthritis Rheum. · Pubmed #12209508 links to  free full text

Abstract: OBJECTIVE: To assay antifilaggrin autoantibodies, we developed an enzyme-linked immunosorbent assay (ELISA) using a "citrullinated" recombinant rat filaggrin. Our objectives were to assess its value for diagnosing rheumatoid arthritis (RA) and to compare the results with those obtained using 4 other reference methods for detection of antifilaggrin autoantibodies, including the commercially available ELISA that uses a modified "citrullinated" synthetic peptide derived from the sequence of human filaggrin (CCP-ELISA). METHODS: We analyzed 711 sera from patients with well-characterized rheumatic diseases, including 240 patients with RA. Antifilaggrin autoantibodies were detected by an ELISA using a recombinant rat filaggrin deiminated in vitro as immunosorbent (ArFA-ELISA). The results considered were the differences between the optical densities obtained on deiminated and nondeiminated proteins. Antibodies to rat esophagus epithelium were detected by indirect immunofluorescence, while antibodies to human filaggrin were detected by immunoblotting and by a recently described ELISA using a deiminated recombinant human filaggrin. Finally, CCP-ELISA was performed according to the manufacturer's recommendations. RESULTS: At the titer thresholds allowing diagnostic specificities of 0.95, 0.985, and 0.99 to be reached, the diagnostic sensitivities of the ArFA-ELISA were 0.76, 0.67, and 0.65, respectively. At these 3 thresholds, the sensitivities were significantly higher than those of the 4 other tests. Despite incomplete overlapping of the 5 tests, the high diagnostic performance of the ArFA-ELISA allows us to propose this test to replace all the other methods for antifilaggrin autoantibody detection. CONCLUSION: ArFA-ELISA appears to be the most efficient test among those available for the detection of antifilaggrin autoantibodies, in terms of diagnostic accuracy for RA. Its diagnostic performance in early RA and its prognostic value are currently under evaluation.

Constantin A, Lauwers-Cancès V, Navaux F, Abbal M, van Meerwijk J, Mazières B, Cambon-Thomsen A, Cantagrel A. · Centre Hospitalier Universitaire Rangueil, INSERM U558, and INSERM U395, Toulouse, France. · Arthritis Rheum. · Pubmed #12124858 links to  free full text

Abstract: OBJECTIVE: To test the hypothesis of an association between a polymorphism in the matrix metalloproteinase 3 (MMP-3) gene promoter and the susceptibility, severity, and progression of rheumatoid arthritis (RA), and to further document the association between HLA-DRB1 alleles encoding the shared epitope (SE) and the severity and progression of RA. METHODS: Patients with early RA (n = 103) were included in this prospective study. A total radiographic damage score (TDS; by the Sharp/van der Heijde method) was used to quantify RA severity at baseline and after 4 years of followup. The 5A/6A biallelic polymorphism in the MMP-3 gene promoter was analyzed using fluorescence-based polymerase chain reaction (PCR). HLA-DRB1 genotyping was performed using PCR methods. Control subjects (n = 127) were unrelated healthy individuals. RESULTS: MMP-3 allele carriage rates and allele and genotype frequencies did not differ between patients and controls. The MMP-3 6A/6A genotype was associated with the highest TDS both at baseline and after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. The DRB1 SE+/+ genotype was associated with the highest TDS after a 4-year followup and with the highest progression of the TDS over the 4 years of followup. Patients homozygous for MMP-3 6A and DRB1 SE had the highest progression of the TDS. CONCLUSION: This study provides the first evidence of an association between a polymorphism in the MMP-3 gene promoter and the severity and progression of RA, but not RA susceptibility. Investigation of this polymorphism could be combined with that of DRB1 gene polymorphism to improve the predictive accuracy and management strategy in early RA.

Cemerski S, Cantagrel A, Van Meerwijk JP, Romagnoli P. · Tolerance and Autoimmunity section, INSERM U563, IFR 30 Institute Claude de Preval, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France. · J Biol Chem. · Pubmed #11916964 links to  free full text

Abstract: Oxidative stress plays an important role in the induction of T lymphocyte hyporesponsiveness observed in several human pathologies including cancer, rheumatoid arthritis, leprosy, and AIDS. To investigate the molecular basis of oxidative stress-induced T cell hyporesponsiveness, we have developed an in vitro system in which T lymphocytes are rendered hyporesponsive by co-culture with oxygen radical-producing activated neutrophils. We have observed a direct correlation between the level of T cell hyporesponsiveness induced and the concentration of reactive oxygen species produced. Moreover, induction of T cell hyporesponsiveness is blocked by addition of N-acetyl cysteine, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride, and catalase, confirming the critical role of oxidative stress in this system. The pattern of tyrosine-phosphorylated proteins was profoundly altered in hyporesponsive as compared with normal T cells. In hyporesponsive T cells, T cell receptor (TCR) ligation no longer induced phospholipase C-gamma1 activation and caused reduced Ca(2+) flux. In contrast, despite increased levels of ERK1/2 phosphorylation, TCR-dependent activation of mitogen-activated protein kinase ERK1/2 was unaltered in hyporesponsive T lymphocytes. A late TCR-signaling event such as caspase 3 activation was as well unaffected in hyporesponsive T lymphocytes. Our data indicate that TCR-signaling pathways are differentially affected by physiological levels of oxidative stress and would suggest that although "hyporesponsive" T cells have lost certain effector functions, they may have maintained or gained others.

Constantin A, Lauwers-Cancès V, Navaux F, Abbal M, van Meerwijk J, Mazières B, Cambon-Thomsen A, Cantagrel A. · Department of Rheumatology and Immunology, CHU Rangueil, France. · J Rheumatol. · Pubmed #11824952 No free full text.

Abstract: OBJECTIVE: Rheumatoid arthritis (RA) is characterized by chronic synovitis leading to permanent damage of the joints. Collagenase-1 (MMP-1) is a matrix metalloproteinase involved in articular cartilage degradation. We investigated the association between a biallelic polymorphism in the MMP-1 gene promoter and the susceptibility to, and severity of, RA. We also investigated the association between HLA-DRB1 gene polymorphism and severity of RA. METHODS: One hundred and three patients with early RA were included in this prospective longitudinal study. A radiographic damage score was used to quantify disease severity at baseline and after 4 years of followup. MMP-1 polymorphism genotyping was analyzed using a fluorescent-based polymerase chain reaction (PCR). HLA-DRB1 genotypes were determined by PCR sequence-specific oligonucleotide probes. One hundred and thirty-three healthy individuals were used as controls. RESULTS: MMP-1 allele and genotype frequencies did not differ between RA patients and controls. The radiographic damage or its progression over the 4 years of followup did not differ across MMP-1 genotypes. The radiographic damage score and its progression over the 4 years of followup differed across HLA-DRB1 genotypes. The HLA-DRB I shared epitope +/+ genotype was associated with the highest radiographic damage score and the highest progression, while the shared epitope -/- genotype was associated with the lowest. CONCLUSION: Our results do not support the hypothesis of an association between this particular polymorphism in the MMP-1 gene promoter and susceptibility to, or severity of, RA. This study confirms the previous reports of an association between the HLA-DRB1 gene polymorphism and severity of RA.

Combe B, Dougados M, Goupille P, Cantagrel A, Eliaou JF, Sibilia J, Meyer O, Sany J, Daurès JP, Dubois A. · Fédération de Rhumatologie, Centre Hospitalier Universitaire Montpellier, and INSERM U475, France. · Arthritis Rheum. · Pubmed #11508423 links to  free full text

Abstract: OBJECTIVE: To determine prognostic factors of radiologic damage and radiologic progression in early rheumatoid arthritis (RA). METHODS: A cohort of 191 patients with RA whose disease duration was shorter than 1 year were prospectively followed up for 3 years. Radiologic scores (as determined by Sharp's method, modified by van der Heijde) and radiologic progression were used as outcome measures. Numerous baseline clinical, laboratory, genetic, and radiographic data were obtained. RESULTS: The change in the total radiologic score for the patients followed up over 3 years was a mean +/- SD increase of 6.1 +/- 6.2. Radiologic progression was observed in 71 of the 172 patients for whom there were data at the end of the study. By univariate analysis with Fisher's exact test, radiologic scores and progression at followup were closely correlated with the baseline values of the erythrocyte sedimentation rate (ESR), C-reactive protein level, IgM and IgA rheumatoid factor positivity, antiperinuclear antibody positivity, radiologic scores, duration of morning stiffness, and RA-associated HLA-DRB1*04 genes. No correlation was demonstrated with sex, age, Disease Activity Score, swollen or tender joint counts, extraarticular manifestations, Health Assessment Questionnaire score, Ritchie Articular Index, patient's assessment of pain, positivity for anti-heat-shock protein 90-kd antibodies, anticalpastatin antibodies, anti-RA33 antibodies, antinuclear antibodies, YKL-40, or antikeratin antibodies, and HLA-DRB1*01 genes. The logistic regression analysis revealed that the only baseline values that were predictive of the 3-year radiologic scores were IgM rheumatoid factor positivity, DRB1*04 genes, pain score, and total radiologic score. Progression of joint damage was predicted by the ESR, IgM rheumatoid factor positivity, DRB1*04 genes, and erosions score at baseline. CONCLUSION: Prognostic factors for radiographic damage in early RA were identified. A combination of these baseline values allowed us to draw up a predictive arithmetic score that could be used to predict radiologic damage at 3 years and radiologic progression in individual patients.

Nogueira L, Sebbag M, Vincent C, Arnaud M, Fournié B, Cantagrel A, Jolivet M, Serre G. · Department of Biology and Pathology of the Cell, Institut National de la Santé et de la Recherche Médicale (CJF 96-02), Toulouse-Purpan School of Medicine, University of Toulouse III (IFR Claude de Préval, INSERM-CNRS-UPS - CHU), France. · Ann Rheum Dis. · Pubmed #11502616 links to  free full text

Abstract: OBJECTIVE: To develop a standardisable enzyme linked immunosorbent assay (ELISA), using human filaggrin, for detection of antifilaggrin autoantibodies in rheumatoid arthritis (RA). To compare the diagnostic performance of the ELISA with those of reference tests: "antikeratin antibodies" ("AKA"), and antibodies to human epidermis filaggrin detected by immunoblotting (AhFA-IB). METHODS: Two ELISAs were developed using either affinity purified neutral-acidic human epidermis filaggrin (AhFA-ELISA-pur) or a recombinant human filaggrin deiminated in vitro (AhFA-ELISA-rec) as immunosorbent. Antifilaggrin autoantibodies were assayed in 714 serum samples from patients with well characterised rheumatic diseases, including 241 RA and 473 other rheumatic diseases, using the two ELISAs. "AKA" and AhFA-IB tests were carried out in the same series of patients. The diagnostic performance of the four tests was compared and their relationships analysed. RESULTS: The titres of "AKA", AhFA-IB, and the AhFA-ELISAs correlated strongly with each other. The diagnostic sensitivity of the AhFA-ELISA-rec, which was better than that of AhFA-ELISA-pur, was 0.52 for a specificity of 0.95. This performance was similar to those of "AKA" or AhFA-IB. However, combining AhFA-ELISA-rec with AhFA-IB led to a diagnostic sensitivity of 0.55 for a specificity of 0.99. CONCLUSION: A simple and easily standardisable ELISA for detection of antifilaggrin autoantibodies was developed and validated on a large series of patients using a citrullinated recombinant human filaggrin. The diagnostic performance of the test was similar to that of the "AKA" and AhFA-IB. Nevertheless, combining the AhFA-ELISA-rec with one of the other tests clearly enhanced the performance.

Romagnoli P, Strahan D, Pelosi M, Cantagrel A, van Meerwijk JP. · Tolerance and Autoimmunity Section, INSERM U395, IFR 30, CHU Purpan, BP 3028, 31024 Toulouse Cedex 3, France. · Int Immunol. · Pubmed #11222499 links to  free full text

Abstract: Rheumatoid arthritis (RA) synovial fluid (SF)-T lymphocytes appear relatively inactive in situ and respond only weakly to diverse stimuli ex vivo. To characterize the molecular defects underlying this hyporesponsiveness we analyzed the expression level of several proteins involved in TCR-proximal signal transduction. As compared to peripheral blood (PB)-T lymphocytes, SF-T cells from some (but not all) of the patients analyzed expressed lower levels of TCRalphabeta, CD3epsilon, TCRzeta, p56(lck) and LAT, while p59(fyn), phospholipase C-gamma1 and ZAP-70 expression was unaltered. Semi-quantitative analysis of T cells from several patients revealed that the degree of TCRzeta chain and p56(lck) modulation correlated statistically significantly with the level of SF-T cell hyporesponsiveness. The differential reactivity of p56(lck) specific monoclonal and polyclonal antibodies in SF-T but not PB-T lymphocytes indicated that p56(lck) modulation consists of a conformational change rather than loss of expression. Our results indicate that multiple signaling molecules can be modulated in RA SF-T cells and show for the first time a direct quantitative correlation between T cell hyporesponsiveness and modulation of TCRzeta and of p56(lck), a critical protein tyrosine kinase required for T cell activation.

Masson-Bessière C, Sebbag M, Durieux JJ, Nogueira L, Vincent C, Girbal-Neuhauser E, Durroux R, Cantagrel A, Serre G. · Department of Biology and Pathology of the Cell, Institut National de la Santé et de la Recherche Médicale (CJF 96-02), Toulouse-Purpan School of Medicine, University of Toulouse III, France. · Clin Exp Immunol. · Pubmed #10691929 links to  free full text

Abstract: IgG anti-filaggrin autoantibodies (AFA) are the most specific serological markers of rheumatoid arthritis (RA). They include the so-called 'anti-keratin antibodies' (AKA) and anti-perinuclear factor (APF), and recognize human epidermal filaggrin and other (pro)filaggrin-related proteins of various epithelial tissues. In this study we demonstrate that AFA are produced in rheumatoid synovial joints. In 31 RA patients, AFA levels were assayed at equal IgG concentrations in paired synovial fluids (SF) and sera. AFA titre-like values determined by indirect immunofluorescence and immunoblotting and AFA concentrations determined by ELISA were non-significantly different in serum and SF, clearly indicating that AFA are not concentrated in SF. In contrast, we demonstrated that AFA are enriched in RA synovial membranes, since the ELISA-determined AFA in low ionic-strength extracts of synovial tissue from four RA patients represented a 7.5-fold higher proportion of total IgG than in paired sera. When small synovial tissue explants from RA patients were cultured for a period of 5 weeks, the profile of IgG and AFA released in the culture supernatants was first consistent with passive diffusion of the tissue-infiltrating IgG (including AFA) over the first day of culture, then with a de novo synthesis of IgG and AFA. Therefore, AFA-secreting plasma cells are present in the synovial tissue of RA patients and AFA can represent a significant proportion of the IgG secreted within the rheumatoid pannus.

Loubet-Lescoulié P, Constantin A, Mazières B, Tkaczuk J, de Préval C, Cantagrel A. · Institut National de la Santé et de la Recherche Médicale, Unité 395, Hôpital Purpan, France. · Scand J Rheumatol. · Pubmed #10503562 No free full text.

Abstract: Currently, few informations are available about spontaneous production of T cell cytokines in rheumatoid arthritis (RA) peripheral blood (PB), because these cytokines are generally under the detection threshold of ELISAs. Because the Th1/Th2 balance could help to determine the outcome of RA, we used a sensitive and quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method to mesure spontaneous T cell production of IL-2, IL-4, IL-10, and IFN-gamma mRNAs using unstimulated PBMC from 25 active RA patients, not taking any DMARDs for at least 6 weeks, and 19 healthy controls. Spontaneous IL-2 and IL-4 mRNA expressions are significantly lower in RA patients compared to healthy controls. Levels of IL-10 and IFN-gamma are similar in the two groups. No correlation was found between cytokine mRNA levels and clinical parameters. Spontaneous IL-4 and IL-10 mRNA levels are respectively correlated to the number of CD4+ T cells and to the number of monocytes in PB. After in vitro stimulation, IFN-gamma mRNA production by RA PBMC is significantly decreased. Most of the patients cannot be classified as having a T cell cytokine type 1 or type 2 secretion pattern in PB. IL-2 and IL-4 mRNAs in PB of active RA are produced at a low spontaneous level and the response to in vitro activation by mitogen is weak.

Cantagrel A, Navaux F, Loubet-Lescoulié P, Nourhashemi F, Enault G, Abbal M, Constantin A, Laroche M, Mazières B. · Service de Rhumatologie, Hôpital Rangueil, Toulouse, France. · Arthritis Rheum. · Pubmed #10366101 links to  free full text

Abstract: OBJECTIVE: To test if interleukin-1beta (IL-1beta), IL-1 receptor antagonist (IL-1Ra), IL-4, or IL-10 gene polymorphisms could be used as markers of susceptibility or severity in rheumatoid arthritis (RA). METHODS: The study included 108 patients with early RA followed up for 2 years and 128 healthy controls. From genomic DNA, 6 polymorphisms in genes for IL-1beta, IL-1Ra, IL-10, and IL-4 were typed. Allelic frequencies and carriage rates were compared between RA patients and controls, between patients with erosive and nonerosive RA, and between patients with or without sustained remission. RESULTS: The RP1 allele of the IL-4 gene was found with a significantly higher frequency in RA patients compared with controls. The combination of an RA-related HLA-DR allele expressing shared epitope and the presence of allele E2 in IL-1beta exon 5 was found to expose patients to an increased risk of erosive disease, with an odds ratio of 8.20 (95% confidence interval 2.59-25.84, P < 0.0001). No significant association was observed between polymorphisms and the occurrence of sustained remission. CONCLUSION: This report, for the first time, indicates an association between RA and a polymorphic IL-4 gene sequence located in 5q31-33. In addition, the results show the prognostic value of a polymorphism in IL-1beta exon 5, which allowed prediction of erosive disease with a specificity of 91.8% in 42.1% of patients. Although these observations are very interesting, they have to be considered preliminary and will need to be confirmed.