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      Biomarkers of Good EULAR Response to the B Cell Depletion Therapy in All Seropositive Rheumatoid Arthritis Patients: Clues for the Pathogenesis

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          Abstract

          Objective

          To find out whether a high number of auto-antibodies can increase the probability of a “good-EULAR response” and to identify the possible biomarkers of response in seropositive rheumatoid arthritis (RA) patients undergoing the B cell depletion therapy (BCDT).

          Patients and Methods

          One hundred and thirty-eight patients with long standing RA (LSRA), 75% non or poorly responsive to one or more TNFα blockers, all seropositive for at least one autoantibody (AAB) (RF-IgM, RF-IgA, RF-IgG, anti-MCV, ACPA-IgG, ACPA-IgA, ACPA-IgM) received one full course of BCDT. The major outcomes (moderate or good-EULAR response) were assessed after 6 months of therapy. The IL6 and BAFF levels were also determined.

          Results

          At a 6-month follow-up, 33 (23.9%) of the RA patients achieved a good EULAR response. Having up to 5-AABs positivity increased the chances for treatment response. After a logistic regression analysis, however, only 4 baseline factors arose as associated with a good-EULAR response: no steroid therapy (OR = 6.25), a lymphocyte count <1875/uL (OR = 10.74), a RF-IgG level >52.1 IU/ml (OR = 8.37) and BAFF levels <1011 pg/ml (OR = 7.38). When all the AABs, except for RF-IgM and ACPA-IgG, were left in the analysis, the two final predictors were no-steroid therapy and low lymphocyte count.

          Discussion

          The number of AABs increased the chances of being a “good-EULAR” responder. The only predictors, however, at the baseline of a good response in this seropositive cohort of RA patients were 2 simple variables – no steroids and lymphocyte count – and two laboratory assays – IgG-RF and BAFF.

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          Most cited references21

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          The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.

          The revised criteria for the classification of rheumatoid arthritis (RA) were formulated from a computerized analysis of 262 contemporary, consecutively studied patients with RA and 262 control subjects with rheumatic diseases other than RA (non-RA). The new criteria are as follows: 1) morning stiffness in and around joints lasting at least 1 hour before maximal improvement; 2) soft tissue swelling (arthritis) of 3 or more joint areas observed by a physician; 3) swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints; 4) symmetric swelling (arthritis); 5) rheumatoid nodules; 6) the presence of rheumatoid factor; and 7) radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints. Criteria 1 through 4 must have been present for at least 6 weeks. Rheumatoid arthritis is defined by the presence of 4 or more criteria, and no further qualifications (classic, definite, or probable) or list of exclusions are required. In addition, a "classification tree" schema is presented which performs equally as well as the traditional (4 of 7) format. The new criteria demonstrated 91-94% sensitivity and 89% specificity for RA when compared with non-RA rheumatic disease control subjects.
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            Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria.

            To validate the European League Against Rheumatism (EULAR), the American College of Rheumatology (ACR), and the World Health Organization (WHO)/International League Against Rheumatism (ILAR) response criteria for rheumatoid arthritis (RA). EULAR response criteria were developed combining change from baseline and level of disease activity attained during follow up. In a trial comparing hydroxychloroquine and sulfasalazine, we studied construct (radiographic progression), criterion (functional capacity), and discriminant validity. EULAR response criteria had good construct, criterion, and discriminant validity, ACR and WHO/ILAR criteria showed only good criterion validity. EULAR response criteria showed better construct and discriminant validity than did the ACR and the WHO/ILAR response criteria for RA.
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              Early effects of rituximab on the synovial cell infiltrate in patients with rheumatoid arthritis.

              To study the specific effects of rituximab treatment on the synovium in patients with rheumatoid arthritis (RA) early after initiation of treatment. Seventeen RA patients underwent an arthroscopic synovial biopsy procedure directly before and 1 month after receiving 2 infusions of the chimeric anti-CD20 monoclonal antibody rituximab (1,000 mg on days 1 and 15; both without methylprednisolone premedication). Immunohistochemical analysis was performed to characterize the cell infiltrate. Stained tissue sections were analyzed by digital image analysis. Statistical analysis was performed using Wilcoxon's signed rank test. No significant change in the Disease Activity Score 28-joint assessment was found at 4 weeks after the first rituximab infusion. At 2 and 4 weeks after infusion, B cells in peripheral blood were almost completely depleted. Most B cells in the synovium were found in large lymphocyte aggregates. Interestingly, a significant reduction in B cell numbers at sites of inflammation was observed 4 weeks after treatment (median 26 cells/mm(2) [interquartile range 4-150] before treatment and 11 cells/mm(2) [interquartile range 0-29] after treatment; P < 0.02). B cells disappeared completely in 3 patients, whereas there was partial depletion in 11 patients. In the other 3 patients, no B cells were present in biopsy tissues obtained either pretreatment or posttreatment. No reductions in other synovial cell populations were observed at 4 weeks. Rituximab treatment leads to a rapid and significant decrease in synovial B cell numbers, but not in all patients. Whether the variable tissue response is related to the clinical response over time remains to be clarified.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                30 July 2012
                : 7
                : 7
                : e40362
                Affiliations
                [1 ]Division of Rheumatology, Catholic University of the Sacred Heart, Rome, Italy
                [2 ]Division of Rheumatology, University of Pavia, IRCCS S. Matteo Foundation, Pavia, Italy
                [3 ]Department of Clinical and Experimental Medicine, Section of Rheumatology and Internal Medicine, University of Verona, Verona, Italy
                [4 ]Rheumatology Unit, Department of Internal Medicine, Ospedale di S. Giovanni di Dio, Florence, Italy
                [5 ]Division of Clinical Immunology and Rheumatology, II School of Medicine, S. Andrea University Hospital, “Sapienza” University of Rome, Rome, Italy
                [6 ]Rheumatology Unit, University Hospital L. Sacco, Milan, Italy
                [7 ]Unit of Hygiene, Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome, Italy
                Innsbruck Medical University, Austria
                Author notes

                Competing Interests: The authors have the following interest: The authors have received funding from a commercial source (Hoffmann-La Roche and Genentech, Inc.) There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

                Conceived and designed the experiments: GF EG BT. Performed the experiments: BT FB-P. Analyzed the data: GF BT EG AM. Contributed reagents/materials/analysis tools: GF CM. Wrote the paper: GF BT EG AM. Collected patients' samples and patients' data: FB-P EG VR MB EP FA DB MM PS-P BL.

                Article
                PONE-D-11-08927
                10.1371/journal.pone.0040362
                3408482
                22859946
                d0b6756b-6b32-40cf-b5b5-32c39703b8ab
                Copyright @ 2012

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 18 January 2012
                : 5 June 2012
                Page count
                Pages: 7
                Funding
                This study was supported by Hoffmann-La Roche, Genentech, Inc. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Immunology
                Immune Cells
                B Cells
                Medicine
                Clinical Immunology
                Immune Response
                Diagnostic Medicine
                Pathology
                General Pathology
                Biomarkers
                Epidemiology
                Biomarker Epidemiology
                Rheumatology
                Rheumatoid Arthritis

                Uncategorized
                Uncategorized

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