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

GREPI CNRS UMR 5525, INSERM IFR 130, Université J Fourier, Grenoble, France.
Annals of the rheumatic diseases (Impact Factor: 10.38). 08/2009; 68(8). DOI: 10.1136/ard.2008.093153
Source: OAI


OBJECTIVES: The use of biologics 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 RA patients (28 non-responders ACR 20 negative and 32 responders ACR 70 positive to infliximab) were studied by SELDI-TOF-MS technology on two types of arrays, an anion exchange array (SAX2) and a nickel affinity array (IMAC3-Ni). Biomarker characterization was carried out using classical biochemical methods (purification by ammonium sulfate precipitation or metal affinity chromatography) and identification by MALDI-TOF 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 both the sensitivity and specificity of the detection of patient response to over 97%. The 28 kDa protein was characterized as apolipoprotein A-I and the 7.77 kDa biomarker was identified as platelet factor 4. CONCLUSIONS: We characterized six plasma biomarkers, 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.

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    • "In this study, nine differentially expressed proteins were identified in RA patients in comparison to healthy control using MALDI TOF-MS/MS suggesting that many proteins are associated with RA. Some of these proteins such as apolipoprotein, albumin, heptoglobulin beta chain are already known to be involved in the development of RA [8], [33], [34]. Recently, significantly higher level (p<0.05) of TTR in RA plasma compared to healthy control has been reported, however, their role in the pathogenesis of RA is not understood. "
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic and inflammatory rheumatic disease that leads to inflammation of the joints and surrounding tissues. Identification of novel protein(s) associated with severity of RA is a prerequisite for better understanding of pathogenesis of this disease that may also have potential to serve as novel biomarkers in the diagnosis of RA. Present study was undertaken to compare the amount of autoantigens and autoantibodies in the plasma of RA patients in comparison to healthy controls. Plasma samples were collected from the patients suffering from RA, Osteoarthritis (OA), Systemic lupus erythematosus (SLE) and healthy volunteers. The screening of plasma proteins were carried out using 2-dimensional gel electrophoresis followed by identification of differentially expressed protein by MALDI-TOF MS/MS. Among several differentially expressed proteins, transthyretin (TTR) has been identified as one of the protein that showed significantly up regulated expression in the plasma of RA patients. The results were further validated by Western blot analysis and ELISA. In comparison to OA synovium, an exclusive significantly high expression of TTR in RA has been validated through IHC, Western blotting and IEM studies. Most importantly, the increase in expression of TTR with the progression of severity of RA condition has been observed. The autoantibodies against TTR present in the RA plasma were identified using immunoprecipitation-Western methods. The significant production of autoantibodies was validated by ELISA and Western blot analysis using recombinant pure protein of TTR. Hence, these novel observations on increase in TTR expression with the increase in severity of RA conditions and significant production of autoantibodies against TTR clearly suggest that a systematic studies on the role TTR in the pathogenesis of RA is immediately required and TTR may be used as a serum diagnostic marker together with other biochemical parameters and clinical symptoms for RA screening and diagnosis.
    PLoS ONE 04/2014; 9(4):e93905. DOI:10.1371/journal.pone.0093905 · 3.23 Impact Factor
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    • "Recently, several prognostic markers for the efficacy of IFX, including plasma platelet factor 4 [26] and the gene or mRNA profile in peripheral blood cells [27,28], have been reported; however, the measurement of these markers is complicated and commercially unavailable, and the prognostic value remains insufficient. Regarding these points, ANA and anti-ds DNA Abs are routine laboratory tests and can be measured easily and simply in daily clinical practice. "
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    ABSTRACT: The induction of antinuclear antibodies (ANAs) or anti-double-stranded (ds) -DNA antibodies (Abs) after infliximab (IFX) therapy in rheumatoid arthritis (RA) is a well-known phenomenon, but the correlation of such Abs with the clinical response to IFX has not yet been determined. The aims of this retrospective observational study were to examine the prevalence of positive ANA and anti-ds-DNA Abs before and after IFX therapy in patients with RA and to investigate whether an increased titer of such Abs is associated with the clinical efficacy of IFX. One hundred eleven RA patients who had received IFX were studied. ANA (indirect immunofluorescence with HEp-2 cells) and anti-ds-DNA Abs (Farr assay) results were examined before and after IFX therapy. The overall clinical response assessed by EULAR response criteria was as follows: good response in 55%, including remission in 38%; moderate response in 18%; and no response (NOR) in 27%. The positivity of ANA (≥ 1:160) and anti-ds-DNA Abs significantly increased from 25% to 40% (P = 0.03) and from 3% to 26% (P < 0.001) after IFX, respectively. EULAR response differed significantly according to the ANA titer before IFX (P = 0.001), and the efficacy of IFX became worse as the ANA titer before starting IFX increased. Furthermore, the differences in the clinical response of the ANA titer before IFX ≤ 1:80 and ≥ 1:160 were significant (good, moderate, and no response were 66%, 9%, and 25% in ≤ 1:80 group versus 26%, 33%, 41% in ≥ 1:160 group, respectively; P < 0.001). In 13 patients whose ANA had increased after IFX, 10 showed NOR, only one showed a good response, and none reached remission. These clinical responses were significantly different from ANA no-change patients. In 21 patients with positive anti-ds-DNA Abs after IFX, 16 showed NOR, only two showed a good response, and none reached remission. The present study suggests that the ANA titer before starting IFX predicts the clinical response to IFX. The increased titers of ANA or anti-ds-DNA Abs after IFX may be useful markers of NOR.
    Arthritis research & therapy 12/2011; 13(6):R213. DOI:10.1186/ar3546 · 3.75 Impact Factor
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    • "Baseline levels of intracellular adhesion molecule-1 (ICAM-1) and cartilage oligomeric matrix protein (COMP) have been associated with response in RA patients treated with adalimumab [6]. More recent studies have identified that apolipoprotein A1 [10], serpin, and S-100-related proteins are associated with response to infliximab treatment [11]. We also recently showed that changes in E-selectin, interleukin (IL)-18, serum amyloid A, and matrix metalloproteinase-9 (MMP-9) are associated with improvement in clinical response measures in a phase 2 study of patients with active RA despite methotrexate (MTX) therapy, who were treated with golimumab (a human monoclonal antibody to TNF-α) [12]. "
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    ABSTRACT: The goal of this study was to identify serum markers that are modulated by treatment with golimumab with or without methotrexate (MTX) and are associated with clinical response. Sera were collected at weeks 0 and 4 from a total of 336 patients (training dataset, n = 100; test dataset, n = 236) from the GO-FORWARD study of patients with active rheumatoid arthritis despite MTX. Patients were randomly assigned to receive placebo plus MTX; golimumab, 100 mg plus placebo; golimumab, 50 mg plus MTX; or golimumab, 100 mg plus MTX. Subcutaneous injections were administered every 4 weeks. Samples were tested for select inflammatory, bone, and cartilage markers and for protein profiling using multianalyte profiles. Treatment with golimumab with or without MTX resulted in significant decreases in a variety of serum proteins at week 4 as compared with placebo plus MTX. The American College of Rheumatology (ACR) 20, ACR 50, and Disease Activity Score (DAS) 28 responders showed a distinct biomarker profile compared with nonresponding patients. ACR 20 and ACR 50 responders among the golimumab/golimumab + MTX-treated patients had a distinct change from baseline to week 4 in serum protein profile as compared with nonresponders. Some of these changed markers were also associated with multiple clinical response measures and improvement in outcome measures in golimumab/golimumab + MTX-treated patients. Although the positive and negative predictive values of the panel of markers were modest, they were stronger than C-reactive protein alone in predicting clinical response to golimumab. identification number: NCT00264550.
    Arthritis research & therapy 11/2010; 12(6):R211. DOI:10.1186/ar3188 · 3.75 Impact Factor
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