Laurent Grange

A 1-year case-control study in patients with rheumatoid arthritis indicates prevention of loss of bone mineral density in both responders and nonresponders to infliximab

The goal of the present study was to record changes in bone mineral density (BMD) and markers of bone turnover in patients with rheumatoid arthritis (RA) who were treated with methotrexate combined (or not combined) with infliximab. Included were 90 patients with RA who required anti-TNF-α therapy with infliximab because of persistent active disease despite treatment with methotrexate. The historical control group included 99 patients with RA who were treated with methotrexate at a time when anti-TNF-α treatment was not yet available. Lumbar and femoral neck BMD was measured using dual energy X-ray absorptiometry at baseline and 1 year later. Osteocalcin, C-terminal cross-linked telopeptide of type I collagen, parathyroid hormone and 25-hydroxycholecalciferol were measured in plasma at baseline and 1 year later. At 1 year BMD had decreased in the control group at spine (P < 0.01) and femoral neck (P < 0.001). In contrast, BMD at spine and femoral neck did not change after 1 year of infliximab treatment. At the same time point, no change in bone remodelling markers was observed. No association was observed between clinical response and changes in BMD, indicating that even those who did not respond clinically did not lose bone over a 1-year period. These data confirm the BMD decrease observed in RA patients treated with methotrexate alone. This bone loss was prevented by infliximab therapy. Importantly, this beneficial effect was also observed in apparent nonresponders.

The shared epitope is a marker of severity associated with selection for, but not with response to, infliximab in a large rheumatoid arthritis population

Objective: To determine whether joint destruction, indication for, and response to infliximab in rheumatoid arthritis are associated with the shared epitope (SE) or selected cytokine gene polymorphisms (interleukin (IL) 1B, IL1-RN, and tumour necrosis α). Methods: In a large rheumatoid arthritis population of 930 patients from the same area (Rhône-Alpes, France), patients with (n = 198) or without infliximab treatment (n = 732) were compared according to their genetic status. Clinical, biological, and radiological data were collected. Typing for SE status and cytokine polymorphisms was carried out using enzyme linked oligosorbent assay. Statistical analysis was by χ2 testing and calculation of odds ratios (OR). Results: A dose relation was observed between the number of SE copies and joint damage in the whole rheumatoid population (OR, 1 v 0 SE copy = 2.38 (95% confidence interval, 1.77 to 3.19), p<0.001; OR 2 v 0 SE copy = 3.92 (2.65 to 5.80), p<0.001. The SE effect increased with disease duration but was not significant before two years. Selection for infliximab treatment (n = 198) was associated with increased disease activity, joint damage, and the presence of the SE with a dose effect. In all, 66.2% patients achieved an ACR20 improvement. No clinical or genetic factors were able to predict the clinical response to infliximab. Conclusions: This post-marketing study in a large cohort of rheumatoid arthritis patients indicates a linkage between rheumatoid arthritis severity, selection for treatment with infliximab, and the presence and dose of the SE.

Local hyperhemia to heating is impaired in secondary Raynaud's phenomenon

Accurate and sensitive measurement techniques are a key issue in the quantification of the microvascular and endothelial dysfunction in systemic sclerosis (SSc). Thermal hyperhemia comprises two separate mechanisms: an initial peak that is axon reflex mediated; and a sustained plateau phase that is nitric oxide dependent. The main objective of our study was to test whether thermal hyperhemia in patients with SSc differed from that in patients with primary Raynauds phenomenon (RP) and healthy controls. In a first study, we enrolled 20 patients suffering from SSc, 20 patients with primary RP and 20 healthy volunteers. All subjects were in a fasting state. Post-occlusive hyperhemia, 0.4 mg sublingual nitroglycerin challenge and thermal hyperhemia were performed using laser Doppler flowmetry on the distal pad of the third left finger. In a second study, thermal hyperhemia was performed in 10 patients with rheumatoid arthritis and 10 patients with primary RP. The thermal hyperhemia was dramatically altered in terms of amplitude and kinetics in patients with SSc. Whereas 19 healthy volunteers and 18 patients with primary RP exhibited the classic response, including an initial peak within the first 10 minutes followed by a nadir and a second peak, this occurred only in four of the SSc patients (p < 0.0001). The 10 minutes thermal peak was 43.4 (23.2 to 63), 42.6 (31 to 80.7) and 27 (14.7 to 51.4) mV/mm Hg in the healthy volunteers, primary RP and SSc groups, respectively (p = 0.01), while the 44°C thermal peak was 43.1 (21.3 to 62.1), 42.6 (31.6 to 74.3) and 25.4 (15 to 52.4) mV/mm Hg, respectively (p = 0.01). Thermal hyperhemia was more sensitive and specific than post-occlusive hyperhemia for differentiating SSc from primary RP. In patients with rheumatoid arthritis, thermal hyperhemia was also altered in terms of amplitude. Thermal hyperhemia is dramatically altered in patients with secondary RP in comparison with subjects with primary RP. Further studies are required to determine the mechanisms of this altered response, and whether it may provide additional information in a clinical setting.

Synovial fluid proteomic fingerprint: S100A8, S100A9 and S100A12 proteins discriminate rheumatoid arthritis from other inflammatory joint diseases

OBJECTIVE We investigated SF and serum proteomic fingerprints of patients suffering from RA, OA and other miscellaneous inflammatory arthritides (MIAs) in order to identify RA-specific biomarkers. METHODS SF profiles of 65 patients and serum profiles of 31 patients were studied by surface-enhanced laser desorption and ionization-time-of-flight-mass spectrometry technology. The most discriminating RA biomarkers were identified by matrix-assisted laser desorption ionization-time of flight and their overexpression was confirmed by western blotting and ELISA. RESULTS Three biomarkers of 10 839, 10 445 and 13 338 Da, characterized as S100A8, S100A12 and S100A9 proteins, were the most up-regulated proteins in RA SF. Their expression was about 10-fold higher in RA SF vs OA SF. S100A8 exhibited a sensitivity of 82% and a specificity of 69% in discriminating RA from other MIAs, whereas S100A12 displayed a sensitivity of 79% and a specificity of 64%. Three peptides of 3351, 3423 and 3465 Da, corresponding to the alpha-defensins-1, -2 and -3, were also shown to differentiate RA from other MIAs with weaker sensitivity and specificity. Levels of S100A12, S100A8 and S100A9 were statistically correlated with the neutrophil count in MIA SF but not in the SF of RA patients. S100A8, S100A9, S100A12 and alpha-defensin expression in serum was not different in the three populations. CONCLUSION The most enhanced proteins in RA SF, the S100A8, S100A9 and S00A12 proteins, distinguished RA from MIA with high accuracy. Possible implication of resident cells in this increase may play a role in RA physiopathology.

Apolipoprotein A-I and platelet factor 4 are biomarkers for Infliximab response in rheumatoid arthritis

Objectives: The use of biologicals such as infliximab has dramatically improved the treatment of rheumatoid arthritis (RA). However, factors predictive of therapeutic response need to be identified. A proteomic study was performed prior to infliximab therapy to identify a panel of candidate protein biomarkers of RA predictive of treatment response. Methods: Plasma profiles of 60 patients with RA (28 non-responders (as defined by the American College of Rheumatology 20% improvement criteria (ACR20)) negative and 32 responders (ACR70 positive) to infliximab) were studied by surface enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS) technology on two types of arrays, an anion exchange array (SAX2) and a nickel affinity array (IMAC3-Ni). Biomarker characterisation was carried out using classical biochemical methods (purification by ammonium sulfate precipitation or metal affinity chromatography) and identification by matrix assisted laser desorption/ionisation time-of-flight (MALDI-TOF) MS analysis. Results: Two distinct protein profiles were observed on both arrays and several proteins were differentially expressed in both patient populations. Five proteins at 3.86, 7.77, 7.97, 8.14 and 74.07 kDa were overexpressed in the non-responder group, whereas one at 28 kDa was increased in the responder population (sensitivity>56%, specificity>77.5%). Moreover, combination of several biomarkers improved the sensitivity and specificity of the detection of patient response to over 97%. The 28 kDa protein was characterised as apolipoprotein A-I and the 7.77 kDa biomarker was identified as platelet factor 4. Conclusions: Six plasma biomarkers are characterised, enabling the detection of patient response to infliximab with high sensitivity and specificity. Apolipoprotein A-1 was predictive of a good response to infliximab, whereas platelet factor 4 was associated with non-responders.

A dynamic exercise programme to improve patients’ disability in rheumatoid arthritis: a prospective randomized controlled trial

OBJECTIVE To evaluate the functional, clinical, radiological and quality of life outcomes of a 4-week dynamic exercise programme (DEP) in RA. METHODS Patients matched on the principal medico-social parameters were randomly assigned to either the DEP or the conventional joint rehabilitation group. Primary end point for judging effectiveness was functional status assessed by HAQ. Secondary outcomes included Nottingham Health Profile (NHP), Arthritis Impact Measurement Scale 2-Short Form (AIMS2-SF) and radiological worsening measured by Simple Narrowing Erosion Score (SENS). Clinical evaluation consisted of disease activity score (DAS 28), cycling aerobic fitness and dexterity. Dexterity was measured using Sequential Occupational Dexterity Assessment (SODA) and Duruoz Hand Index (DHI). Data were collected at baseline 1, 6 and 12 months. RESULTS Fifty patients were enrolled. HAQ improved throughout the length of the trial in the DEP group. This improvement was greater in DEP than in the standard joint rehabilitation group at 1 month (-0.2 vs no variation from baseline, P = 0.04), but not at 6 months (-0.2 vs -0.1 in control group, P = 0.25) or 12 months (-0.1 vs no variation in control group, P = 0.51). DEP improved NHP (-23 vs + 7% in control group, P = 0.01) and aerobic fitness (+0.3 vs + 0.1 km per 5 min in control group, P = 0.02) at 1 month but the progress was not statistically significant thereafter. DEP also improved DHI, SODA, DAS 28 and AIMS2-SF, although not significantly. CONCLUSION DEP was effective on functional status assessed by HAQ, quality of life and aerobic fitness at 1 month.

Reproducibility of joint swelling assessments in long-lasting rheumatoid arthritis: Influence on disease activity score-28 values (SEA-repro study part I)

Objectives. To evaluate the reproducibility of clinical synovitis assessments in rheumatoid arthritis and the effect of variability on the Disease Activity Score-28 (DAS28). Methods. Seven healthcare professionals from different cities examined the same patients with active non-early rheumatoid arthritis (RA; duration > 4 yrs), for whom a treatment change was being considered. There was no training session and the examination was to be performed as quickly as possible. The healthcare professionals assessed the 28 joints of the DAS28 in 7 patients (196 joints), then reexamined the same 28 joints in 4 of these 7 patients (112 joints), who had been rendered unrecognizable. Then 7 sonographers examined each of the 7 patients twice, using B-mode and power Doppler ultrasound (PD). The reference standards were presence of synovitis according to at least 50% of clinical examiners and 50% of sonographers. Agreement was assessed by Cohen’s kappa statistic. Results. Intraobserver reliability ranged from 0.31 (least experienced research technician) to 0.77 (most experienced physician). Interobserver reliability ranged from 0.18 to 0.62. The largest difference between the lowest and the highest swollen joint counts in the same patient was 15, and the greatest variation in the DAS28 score was 0.92. Agreement between clinical and sonographic reference standards was 0.46, 0.37, and 0.36 for B-mode, PD, and both, respectively. Conclusion. Clinical inter- and intraobserver reliability is highly dependent on the examiner. Consequences on the DAS28 score can be substantial. Agreement with sonography is poor when both B-mode and PD are used but seems better, although low, when B-mode is used alone.

Reproducibility of Joint Swelling Assessment by Sonography in Patients with Long-lasting Rheumatoid Arthritis (SEA-Repro Study Part II)

Objective. To evaluate the intraobserver and interobserver reproducibility of B-mode and power Doppler (PD) sonography in patients with active long-standing rheumatoid arthritis (RA) comparatively with clinical data. Methods. In each of 7 patients being considered for a change in their RA treatment regimen, 7 healthcare professionals examined the 28 joints used in the Disease Activity Score 28-joint count (DAS28). Then 7 sonographers examined each of the 7 patients twice, using previously published B-mode and PD grading systems. The clinical reference standard was presence of synovitis according to at least 4/7 examiners. The sonographic reference standard was at least grade 1 (ALG1) or 2 (ALG2) synovitis according to at least 4/7 sonographers. Interobserver reproducibility of sonography was assessed versus the sonographer having the best intraobserver reproducibility. Agreement was measured by Cohen’s kappa statistic. Results. Intraobserver and interobserver reproducibility of B-mode and PD used separately was fair to good. Agreement between clinicians and sonographers at all sites using B-mode, PD, and both was 0.46, 0.37, and 0.36, respectively, for grade 1 synovitis; and 0.58, 0.19, and 0.19 for grade 2 synovitis. The number of joints with synovitis was smaller by physical examination (36.7%) than by B-mode with ALG1 (58.6%; p < 0.001). The number of joints with synovitis was higher by physical examination than by PD with both ALG1 (17.8%; p < 0.0001) and ALG2 (6.6%; p < 0.0001). Conclusion. PD findings explain most of the difference between clinical and sonographic joint assessments for synovitis in patients with long-standing RA.

Intervertebral disk degeneration and herniation: the role of metalloproteinases and cytokines.

This article reviews the role of metabolic factors, including metalloproteinases and cytokines, in the occurrence of degenerative disk disease and disk herniation. Given that mechanical factors alone cannot cause disk degeneration, studies must explore metabolic, genetic, nutritional, and age-related factors. Zinc metalloproteinases exert particularly important effects, not only directly, but also indirectly through promotion of neovascularization. The production of these enzymes is dependent on a number of cytokines and on the cell changes they induce. This complex effect acts both on disk matrix degeneration and on the pain generated by contact between the protruding disk and the nerve roots. However, it can have a favorable effect by promoting resorption of the herniated disk. Available data on the role for mechanical factors on the disk chondrocyte metabolism and on metalloproteinase production show that mechanical and metabolic factors interact closely to produce disk disorders.

Factors Influencing Concordance Between Clinical and Ultrasound Findings in Rheumatoid Arthritis

Objective. Clinical joint examination (CJE) is less time-consuming than ultrasound (US) in rheumatoid arthritis (RA). Low concordance between CJE and US would indicate that the 2 tests provide different types of information. Knowledge of factors associated with CJE/US concordance would help to select patients and joints for US. Our objective was to identify factors associated with CJE/US concordance. Methods. Seventy-six patients with RA requiring tumor necrosis factor-α (TNF-α) antagonist therapy were included in a prospective, multicenter cohort. In each patient, 38 joints were evaluated. Synovitis was scored using CJE, B-mode US (B-US), and power Doppler US (PDUS). Joints whose kappa coefficient (κ) for agreement CJE/US was < 0.1 were considered discordant. Multivariate analysis was performed to identify factors independently associated with CJE/US concordance, defined as factors yielding p < 0.05 and OR > 2. Results. Concordance before TNF-α antagonist therapy varied across joints for CJE/US (κ = −0.08 to 0.51) and B-US/PDUS (κ = 0.30 to 0.67). CJE/US concordance was low at the metatarsophalangeal joints and shoulders (κ < 0.1). Before TNF-α antagonist therapy, a low 28-joint Disease Activity Score (DAS28) was associated with good CJE/B-US concordance, and no factors were associated with CJE/PDUS concordance. After TNF-α antagonist therapy, only the joint site was associated with CJE/B-US concordance; joint site and short disease duration were associated with CJE/PDUS concordance. Conclusion. Concordance between CJE and US is poor overall. US adds information to CJE, most notably at the metatarsophalangeal joints and shoulders. Usefulness is decreased for B-US when DAS28 is low and for PDUS when disease duration is short.