Alain Daragon

Gene profiling in white blood cells predicts infliximab responsiveness in rheumatoid arthritis

As indicators of responsiveness to a tumour necrosis factor (TNF)α blocking agent (infliximab) are lacking in rheumatoid arthritis, we have used gene profiling in peripheral blood mononuclear cells to predict a good versus poor response to infliximab. Thirty three patients with very active disease (Disease Activity Score 28 >5.1) that resisted weekly methotrexate therapy were given infliximab at baseline, weeks 2 and 6, and every 8th week thereafter. The patients were categorized as responders if a change of Disease Activity Score 28 = 1.2 was obtained at 3 months. Mononuclear cell RNAs were collected at baseline and at three months from responders and non-responders. The baseline RNAs were hybridised to a microarray of 10,000 non-redundant human cDNAs. In 6 responders and 7 non-responders, 41 mRNAs identified by microarray analysis were expressed as a function of the response to treatment and an unsupervised hierarchical clustering perfectly separated these responders from non-responders. The informativeness of 20 of these 41 transcripts, as measured by qRT-PCR, was re-assessed in 20 other patients. The combined levels of these 20 transcripts properly classified 16 out of 20 patients in a leave-one-out procedure, with a sensitivity of 90% and a specificity of 70%, whereas a set of only 8 transcripts properly classified 18/20 patients. Trends for changes in various transcript levels at three months tightly correlated with treatment responsiveness and a down-regulation of specific transcript levels was observed in non-responders only. Our gene profiling obtained by a non-invasive procedure should now be used to predict the likely responders to an infliximab/methotrexate combination.

Impact of Three Anti-TNFα Biologics on Existing and Emergent Autoimmunity in Rheumatoid Arthritis and Spondylarthropathy Patients

ObjectiveThe objective of this study was to analyze the effects of 3 anti-TNFα agents on markers of autoimmunity in rheumatoid arthritis (RA) and spondylarthropathy (SPA) patients.MethodsFirst-time anti-TNFα biologics (infliximab, etanercept, or adalimumab) were prescribed to 156 RA and 95 SPA (58 ankylosing spondylarthritides, 37 psoriatic arthritides). During 1–2xa0years of follow-up, clinical, biological [antinuclear (ANA) and anti-double-stranded (dsDNA) antibodies, rheumatoid factors (RF), and anti-cyclic citrullinated peptide (CCP) for RA], and therapeutic data were collected biannually.ResultsANA appeared or ANA and anti-dsDNA titers increased significantly (Pu2009<u20090.001) more under infliximab than etanercept in both rheumatisms and than adalimumab in RA patients. During the 2-year follow-up, ANA appeared more in RA patients taking adalimumab than etanercept (Pu2009=u20090.003), but independently of the anti-TNFα used; anti-dsDNA titers rarely became positive. Under etanercept or infliximab, ANA and anti-dsDNA were not influenced by the underlying pathology nor were they affected by infliximab intensification over 18xa0months. Only one case of cutaneous lupus was observed in a patient having IgG anti-dsDNA. The therapeutic responses were independent of ANA and anti-dsDNA titers for all rheumatisms and biologics. In RA patients, RF titers, but not anti-CCP levels, declined with the therapeutic response for all biologics.ConclusionThis is the first study that has evaluated the impact of three TNFα blockers on ANA and anti-dsDNA antibodies in RA and SPA patients. Autoimmunity was more induced with infliximab than etanercept and to a lesser degree to adalimumab but, more importantly, this emergent autoimmunity was exceptionally associated to clinical manifestations of lupus.

Gene profiling predicts rheumatoid arthritis responsiveness to IL-1Ra (anakinra)

OBJECTIVESnThe overall non-response rate to biologics remains 30-40% for patients with RA resistant to MTX. The objective of this study was to predict responsiveness to the anakinra-MTX combination by peripheral blood mononuclear cell gene profiling in order to optimize treatment choice.nnnMETHODSnThirty-two patients treated with anakinra (100u2009mg/day s.c.) and MTX were categorized as responders when their 28-joint DAS (DAS-28) had decreased by ≥1.2 at 3 months. Pre-treatment blood samples had been drawn.nnnRESULTSnFor seven responders and seven non-responders, 52 microarray-identified mRNAs were expressed as a function of the response to treatment, and unsupervised hierarchical clustering correctly separated responders from non-responders. The levels of seven of these 52 transcripts, as assessed by real-time, quantitative RT-PCR, were able to accurately classify 15 of 18 other patients (8 responders and 10 non-responders), with 87.5% specificity and 77.8% negative-predictive value for responders. Among the 52 genes, 56% were associated with IL-1β.nnnCONCLUSIONnThis predictive gene expression profile was obtained with a non-invasive procedure. After further validation in other cohorts of patients, it could be proposed and used on a large scale to select likely RA responders to combined anakinra-MTX. Trial registration. Clinical Trials; NCT00213538 (http://www.clinicaltrials.gov).

Prospective X-ray densitometry and ultrasonography study of the hand bones of patients with rheumatoid arthritis of recent onset

OBJECTIVEnBone demineralization observed in early rheumatoid arthritis is not easily measured. To measure bone loss and to discriminate between rheumatoid arthritis and other rheumatic diseases, we used two methods: dual-energy X-ray absorptiometry and ultrasonography.nnnMETHODSnFrom a population-based recruitment, 32 patients with early peripheral polyarthritis (median disease duration: 4 months) were studied. Clinical, laboratory, functional, hand-bone assessments were made at the entry an at months 6 and 12. Bone X-ray densitometry measurements were made on 16 areas of the hand. Speed of sound was measured across the proximal phalanges of the four fingers. X-rays of both hands were scored according to the modified Sharps score. At 12 months, patients were classified as rheumatoid arthritis (N = 15; 9 F) or as other rheumatic diseases.nnnRESULTSnWe found: 1) significantly decreased bone mineral density (BMD) of the whole hand, in the rheumatoid arthritis group versus the other rheumatic diseases group, at 6 and 12 months (P < 0.05); 2) no significant decrease of bone mineral density (BMD) in other areas in the rheumatoid arthritis group; 3) no significant change of ultrasounds in either group; and 4) no significant correlation between the decrease of BMD in the rheumatoid arthritis group and clinical, biological or radiologic parameters, except for IFNgamma, whose production in whole blood cell culture was lower at entry in the rheumatoid arthritis group.nnnCONCLUSIONnDEXA bone assessment in rheumatoid arthritis was able t detect bone loss in the whole hand at 6 months.

A 3 mg/kg starting dose of infliximab in active spondyloarthritis resistant to conventional treatments is efficient, safe and lowers costs

OBJECTIVEnWe assessed the efficacy, tolerance and cost of a 3 mg/kg starting dose of infliximab for ankylosing spondylitis (AS) and psoriatic arthritis (PsA).nnnMETHODSnWe retrospectively followed-up 45 biologic-naive consecutive patients (11 with axial AS, 24 with axial and peripheral [mixed] AS and 10 with PsA) who were treated between 2002 and 2005 with a 3 mg/kg dose of infliximab after failure of conventional therapies. The following variables were recorded: visual analog scale (VAS) scores of patients global (G) and pain (P) assessment, duration of early morning stiffness (EMS), disease activity (BASDAI) and functional disability (BASFI). Treatment responses were assessed at 6 and 12 months using the AS assessment score (ASAS)-20% and -40% criteria and BASDAI-50.nnnRESULTSnBaseline characteristics of the 29 men and 16 women were (median [range]): G-VAS, 70 [13-100]; P-VAS, 70 [13-100]; EMS, 60 [0-180] minutes; BASDAI, 64.4 [23.9-100]; BASFI, 57.2 [3.5-98.5]. All manifestations regressed significantly (p<0.0001) for 39 (86.7%) and 24 (53.5%) patients at 6 and 12 months, respectively; 26 (57.8%) had achieved ASAS-20 responses at 6 months that persisted at 1 year for 20 (44.4%); 19 (42.2%) and 12 (26.7%) satisfied BASDAI 50 criteria at 6 and 12 months, respectively. Interestingly, almost 30% still received low-dose infliximab after 4 years of follow-up.nnnCONCLUSIONnAn initial dose of 3 mg/kg of infliximab significantly attenuated AS and PsA manifestations in>40% of the patients, making use of this dose highly advantageous in terms of safety and 33% lower cost.

Efficacy of anti-TNF in patients with spondyloarthritis in absence of any imaging sign

OBJECTIVEnSome clinical pictures satisfy spondyloarthritis criteria without any detected imaging signs and the question sometimes arises in clinical daily practice if biologics should be started. Our aim was to evaluate anti-TNF efficacy in patients with clinical but not imaging (radiographic, CT-scan, MRI) signs of spondyloarthritis.nnnMETHODSnThis retrospective study concerned patients with axial spondyloarthritis fulfilling European Spondyloarthritis Study Group (ESSG) criteria, treated with anti-TNF after failure of conventional therapies. Therapeutic responses, rated according to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)-50% or 20 mm and ASAS-20 or -40 definitions, were evaluated after 12 months. Factors associated with those responses were also sought. Propensity score was used to check thereafter whether there were interactions with some baseline variables.nnnRESULTSnAmong 385 patients included, 257 with imaging signs had significantly more frequent therapeutic responses (P=0.0005). About 40% of the spondyloarthritis patients without imaging signs responded to anti-TNF. The response rate was significantly higher in HLA-B27 carriers with initial imaging signs (P=0.028). Furthermore, responders were younger at biotherapy onset, with lower Bath Ankylosing Spondylitis Functional Index (BASFI) and pain visual analog scale score, and higher C-reactive protein (CRP), compared to non-responders. After weighted calculation, the prediction of response to TNF-blockers was quite similar in both groups.nnnCONCLUSIONnThe percentage of patients with exclusively clinical signs who responded to anti-TNF was far from negligible. Regardless the HLA-B27 status, having imaging signs of spondyloarthritis does not provide a superiority of response to anti-TNF compared to the absence of imaging sign. The absence of any imaging sign in patients with spondyloarthritis should therefore not lead to the exclusion of anti-TNF therapy.

Osteocalcin is not a marker of progress in multiple myeloma

Abstract: The aim of this study was to evaluate the usefulness of serum osteocalcin (OC) levels in multiple myeloma (MM) in order to assess its significance and activity, and to predict its course. Serum OC was measurement in 117 patients with MM and 116 healthy controls matched for age and sex. Serum OC levels were weakly correlated with Karnofsky index (r = 0.22; p<0.03). Lowest OC levels were observed when lytic bone lesions increased (p <0.05). There was no relationship between serum OC levels and vertebral crush fractures, serum calcium concentrations or stage of MM, neither was there any relationship between initial serum OC levels and survival. Progression of the disease was associated with a clear fall of serum OC in 61.5% of the “progressive” patients, versus 41% of the persisting “stabilized” cases. Serum OC level was strongly correlated with bone formation (p = 0.005), but not with bone resorption. Serum OC level is a sensitive marker of osteoblast activity, but a poor marker of the severity of MM. We do not consider it as a marker of MM activity or prognosis.

Combining anti-cyclic citrullinated peptide with the American College of Rheumatology 1987 criteria failed to improve early rheumatoid arthritis diagnosis in the community-based very early arthritis cohort

OBJECTIVESnTo test the performances of combining anti-CCP second generation (CCP2) with ACR 1987 classification criteria and to diagnose early RA in a community-based very early arthritis (VErA) patient cohort.nnnMETHODSnThe VErA cohort comprised 310 patients (median age 52 years; 68.1% women; median symptom duration 4.2 months; glucocorticoid- and DMARD naïve) conservatively treated during the first 2 years. At 6 years of follow-up, a three-expert committee classified the patients into three groups: RA, other classified arthritis (OCA) or unclassified arthritis (UA). We calculated the performances of the different sets, including anti-CCP2 positivity, while retaining or deleting RF and rheumatoid nodule components with ACR 1987 criteria for early RA diagnosis. Models were subjected to receiver operating characteristics curve and logistic regression analyses to try to identify relevant sets able to classify very early RA.nnnRESULTSnAt 6 years, 149 patients were diagnosed as RA and 119 as non-RA (95 OCA and 24 UA). The original ACR 1987 criteria had 77.9% sensitivity and 64.7% specificity for the RA diagnosis at 6 years. The modified set excluding rheumatoid nodules, including anti-CCP2 positivity and retaining RF performed significantly better than ACR 1987 criteria, with 79.9% sensitivity and 64.7% specificity and with a larger area under the curve. However, in the zone of interest, i.e., ≥4/7 criteria, the curves for these sets were superimposed.nnnCONCLUSIONSnAdding anti-CCP2 positivity and deleting rheumatoid nodules failed to improve the performances of ACR 1987 classification criteria for the diagnosis of early RA.

Switching from an anti-TNF monoclonal antibody to soluble TNF-receptor yields better results than vice versa: An observational retrospective study of 72 rheumatoid arthritis switchers

OBJECTIVESnTo evaluate the benefits for rheumatoid arthritis (RA) patients of switching from one tumor necrosis factor inhibitor (TNFi) to another based on reason for change (primary failure, escape or intolerance) and molecule-switching order.nnnMETHODSnBetween 2000 and 2008, 356xa0RA patients prescribed a TNFi (infliximab [IFX], etanercept [ETA] or adalimumab [ADA]) and undergoing standardized evaluation were included in this retrospective study. Detailed demographic, clinical and biological data were collected before first biologic use and ≤6xa0months later to evaluate response based on EULAR-criteria. Primary failure, escape or intolerance of first TNFi triggered switch to another TNFi, the response of which was evaluated 6xa0months later. Propensity score then measured any interaction with baseline variables.nnnRESULTSnOf the 356xa0RA patients, 38 switched from IFX/ADA to ETA, 26 from ETA to IFX/ADA, and eight from one monoclonal antibody (mAb; IFX/ADA) to another. Clinical parameters for switchers and non-switchers were comparable. Switchers changed therapies because of primary failure (36.1%), escape (33.3%), or intolerance (30.6%), with no difference found in these subgroups. More switchers responded to the second TNFi than the first (P<0.01), respectively, regardless of switch (ETA to IFX/ADA: 50 vs. 23.1% [P<0.05]; IFX/ADA to ETA: 57.9 vs. 15.8% [P<0.001]) or reason for changing. In addition, DAS28 decreased more with the second antagonist (P<0.001) and regardless of molecules switched (P<0.01). Survival of the second TNFi was significantly longer with switch from mAb to the soluble receptor than vice versa (P<0.05).nnnDISCUSSIONnOverall, any switching from one TNFi to another, especially mAb to soluble receptor, was often beneficial for RA patients.

Synovium CD20 expression is a potential new predictor of bone erosion progression in very-early arthritis treated by sequential DMARDs monotherapy – A pilot study from the VErA cohort

OBJECTIVEnBecause available biomarkers (rheumatoid factors [RF], anti-cyclic citrullinated autoantibodies [anti-CCP2], erythrocyte sedimentation rate at 1st hour [ESR]/C-reactive peptide [CRP] and bone erosions) are insufficient to predict rheumatoid arthritis (RA) structural damage, to determine whether synovium expression of greater or equal to 1 markers could constitute new prognostic factor(s).nnnMETHODnThe study was conducted on 18 prospectively enrolled disease-modifying anti-rheumatic drug (DMARD)- and glucocorticoid-naïve, VErA cohort patients with very-early arthritis (median duration: 4months). Recorded at baseline were: clinical and biological (serum ESR, CRP, RF-isotypes, anti-CCP2, osteoprotegerin, receptor activator of nuclear κB-ligand [RANK-L] and cartilage oligomeric matrix protein [COMP] levels) data; synovium expression (HLA-DR, CD163, CD3, CD20, VEGF, osteoprotegerin, RANK-L, Bcl2 and global inflammation index) for a metacarpophalangeal joint-synovium biopsy. Baseline and 3-year hand-and-foot X-rays were graded with the van der Heijde-modified-Sharp score; the judgment criterion was its progression during follow-up. Pearsons product moment correlation statistics were used to test for association between paired samples.nnnRESULTSnA baseline, a significant relationship was found between erosive damage and markers of B-cell activation, notably the synovium CD20 expression (r=0.68; P=0.0001). Quantified by the modified-Sharp erosion score variation, the 3-year structural damage progression was significantly correlated with: serum levels of RF-IgG (r=0.75; P=0.0003), -IgM (r=0.69; P=0.001), anti-CCP2 (r=0.53; P=0.02) and RANK-L (r=0.61; P=0.007); synovium CD20 expression (r=0.70; P=0.001).nnnCONCLUSIONnThis analysis of the prognostic value of a large panel of synovium markers in a limited sample of prospectively followed, well-documented patients suggested that both synovial CD20 and serum RANK-L levels might be new predictors of structural damage progression in very-early RA.