CAMILLE PINTO FIGUEIREDO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina
LIM/17 - Laboratório de Investigação em Reumatologia, Hospital das Clínicas, Faculdade de Medicina
LIM/17 - Laboratório de Investigação em Reumatologia, Hospital das Clínicas, Faculdade de Medicina
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- Treatment tapering and stopping in patients with rheumatoid arthritis in stable remission (RETRO): a multicentre, randomised, controlled, open-label, phase 3 trial(2021) TASCILAR, Koray; HAGEN, Melanie; KLEYER, Arnd; SIMON, David; REISER, Michaela; HUEBER, Axel J.; MANGER, Bernhard; ENGLBRECHT, Matthias; FINZEL, Stephanie; TONY, Hans-Peter; SCHUCH, Florian; KLEINERT, Stefan; WENDLER, Joerg; RONNEBERGER, Monika; FIGUEIREDO, Camille P.; COBRA, Jayme F.; FEUCHTENBERGER, Martin; FLECK, Martin; MANGER, Karin; OCHS, Wolfgang; SCHMITT-HAENDLE, Matthias; LORENZ, Hanns-Martin; NUESSLEIN, Hubert; ALTEN, Rieke; KRUGER, Klaus; HENES, Joerg; SCHETT, Georg; RECH, JuergenBackground Owing to increasing remission rates, the management of patients with rheumatoid arthritis in sustained remission is of growing interest. The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated tapering and withdrawal of disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis in stable remission to test whether remission could be retained without the need to take DMARD therapy despite an absence of symptoms. Methods RETRO was an investigator-initiated, multicentre, prospective, randomised, controlled, open-label, parallel group phase 3 trial in patients aged at least 18 years with rheumatoid arthritis for at least 12 months before randomisation who were in sustained Disease Activity Score using 28 joints with erythrocyte sedimentation rate (ESR) remission (score <2middot6 units). Eligible patients were recruited consecutively from 14 German hospitals or rheumatology practices and randomly assigned (1:1:1) without stratification and regardless of baseline treatment, using a sequence that was computer-generated by the study statistician, to continue 100% dose DMARD (continue group), taper to 50% dose DMARD (taper group), or 50% dose DMARD for 6 months before stopping DMARDs (stop group). Neither patients nor investigators were masked to the treatment assignment. Patients were assessed every 3 months and screened for disease activity and relapse. The primary endpoint was the proportion of patients in sustained DAS28-ESR remission without relapse at 12 months, analysed using a log-rank test of trend and Cox regression. Analysis by a trained statistician of the primary outcome and safety was done in a modified intention-to treat population that included participants with non-missing baseline data. This study is completed and closed to new participants and is registered with ClinicalTrials.gov (NCT02779114). Findings Between May 26, 2010, and May 29, 2018, 303 patients were enrolled and allocated to continue (n=100), taper (n=102), or stop DMARDs (n=101). 282 (93%) of 303 patients were analysed (93 [93%] of 100 for continue, 93 [91%] of 102 for taper, and 96 [95%] of 101 for stop). Remission was maintained at 12 months by 81middot2% (95% CI 73middot3-90middot0) in the continue group, 58middot6% (49middot2-70middot0) in the taper group, and 43middot3% (34middot6-55middot5) in the stop group (p=0middot0005 with log-rank test for trend). Hazard ratios for relapse were 3middot02 (1middot69-5middot40; p=0middot0003) for the taper group and 4middot34 (2middot48-7middot60; p<0.0001)) for the stop group, in comparison with the continue group. The majority of patients who relapsed regained remission after reintroduction of 100% dose DMARDs. Serious adverse events occurred in ten of 93 (11%) patients in the continue group, seven of 93 (8%) patients in taper group, and 13 of 96 (14%) patients in the stop group. None were considered to be related to the intervention. The most frequent type of serious adverse event was injuries or procedural complications (n=9). Interpretation Reducing antirheumatic drugs in patients with rheumatoid arthritis in stable remission is feasible, with maintenance of remission occurring in about half of the patients. Because relapse rates were significantly higher in patients who tapered or stopped antirheumatic drugs than in patients who continued with a 100% dose, such approaches will require tight monitoring of disease activity. However, remission was regained after reintroduction of antirheumatic treatments in most of those who relapsed in this study. These results might help to prevent overtreatment in a substantial number of patients with rheumatoid arthritis. Funding None.
- Age- and Sex-Dependent Changes of Intra-articular Cortical and Trabecular Bone Structure and the Effects of Rheumatoid Arthritis(2017) SIMON, David; KLEYER, Arnd; STEMMLER, Fabian; SIMON, Christoph; BERLIN, Andreas; HUEBER, Axel J.; HASCHKA, Judith; RENNER, Nina; FIGUEIREDO, Camille; NEUHUBER, Winfried; BUDER, Thomas; ENGLBRECHT, Matthias; RECH, Juergen; ENGELKE, Klaus; SCHETT, GeorgThe objective of this cross-sectional study was to define normal sex- and age-dependent values of intra-articular bone mass and microstructures in the metacarpal heads of healthy individuals by high-resolution peripheral quantitative computed tomography (HR-pQCT) and test the effect of rheumatoid arthritis (RA) on these parameters. Human cadaveric metacarpal heads were used to exactly define intra-articular bone. Healthy individuals of different sex and age categories and RA patients with similar age and sex distribution received HR-pQCT scans of the second metacarpal head and the radius. Total, cortical, and trabecular bone densities as well as microstructural parameters were compared between 1) the different ages and sexes in healthy individuals; 2) between metacarpal heads and the radius; and 3) between healthy individuals and RA patients. The cadaveric study allowed exact definition of the intra-articular (intracapsular) bone margins. These data were applied in measuring intra-articular and radial bone parameters in 214 women and men (108 healthy individuals, 106 RA patients). Correlations between intra-articular and radial bone parameters were good (r=0.51 to 0.62, p<0.001). In contrast to radial bone, intra-articular bone remained stable until age 60 years (between 297 and 312mg HA/cm(3)) but decreased significantly (p<0.001) in women thereafter (237.5 +/- 44.3) with loss of both cortical and trabecular bone. Similarly, RA patients showed significant (p<0.001) loss of intra-articular total (263.0 +/- 44.8), trabecular (171.2 +/- 35.6), and cortical bone (610.2 +/- 62.0) compared with sex- and age-adjusted controls. Standard sex- and age-dependent values for physiological intra-articular bone were defined. Postmenopausal state and RA led to significant decrease of intra-articular bone. (c) 2016 American Society for Bone and Mineral Research.
- HR-pQCTin vivoimaging of periarticular bone changes in chronic inflammatory diseases: Data from acquisition to impact on treatment indications(2021) FIGUEIREDO, Camille P.; PEREZ, Mariana O.; SALES, Lucas Peixoto; SCHETT, Georg; PEREIRA, Rosa M. R.Imaging is essential for the assessment of bone and inflammatory joint diseases. There are several imaging techniques available that differ regarding resolution, radiation exposure, time expending, precision, cost, availability or ability to predict disease progression. High-resolution peripheral quantitative computed tomography (HR-pQCT) that was introduced in 2004 allows thein vivoevaluation of peripheral bone microarchitecture and demonstrated high precision in assessing bone changes in inflammatory musculoskeletal diseases. This review summarizes the use of HR-pQCT for the evaluation of the hand skeleton in inflammatory joint diseases. We conducted a review of the literature regarding the protocols that involve hand joints assessment and evaluation of bone changes as erosions and osteophytes in chronic inflammatory diseases. Apart from measuring bone density and structure of the radius and the tibia, HR-pQCT has contributed to assessment of bone erosions and osteophytes, considered the hallmark of diseases as rheumatoid arthritis and psoriatic arthritis, respectively. In this way, there are some conventions recently established by rheumatic study groups that we just summarized here in order to standardize HR-pQCT measurements.
- Transcriptomic characterization of classical monocytes highlights the involvement of immuno-inflammation in bone erosion in Rheumatoid Arthritis(2023) SALES, Lucas Peixoto; HOUNKPE, Bidossessi Wilfried; PEREZ, Mariana Ortega; CAPARBO, Valeria Falco; DOMICIANO, Diogo Souza; BORBA, Eduardo Ferreira; SCHETT, Georg; FIGUEIREDO, Camille Pinto; PEREIRA, Rosa Maria RodriguesIntroduction: Evidence-based data suggest that under inflammatory conditions, classical monocytes are the main source of osteoclasts and might be involved in bone erosion pathophysiology. Here, we analyze the transcriptomic profile of classical monocytes in erosive and non-erosive rheumatoid arthritis patients in order to better understand their contribution to bone erosion.Methods: Thirty-nine premenopausal RA patients were consecutively enrolled and divided into two groups based on the presence of bone erosions on hand joints. Classical monocytes were isolated from peripheral blood through negative selection, and RNA-seq was performed using a poly-A enrichment kit and Illumina (R) platform. Classical monocytes transcriptome from healthy age-matched women were also included to identify differentially expressed genes (DEGs). Therefore, gene sets analysis was performed to identify the enriched biological pathways.Results: RNA-seq analysis resulted in the identification of 1,140 DEGs of which 89 were up-regulated and 1,051 down-regulated in RA patients with bone erosion compared to those without bone erosions. Among up-regulated genes, there was a highlighted expression of IL18RAP and KLF14 related to the production of pro-inflammatory cytokines, innate and adaptive immune response. Genes related to collagen metabolism (LARP6) and bone formation process (PAPPA) were down-regulated in RA patients with erosions. Enriched pathways in patients with erosions were associated with greater activation of immune activation, and inflammation. Interestingly, pathways associated with osteoblast differentiation and regulation of Wnt signaling were less activated in RA patients with erosions.Conclusion: These findings suggest that alterations in expression of monocyte genes related to the inflammatory process and impairment of bone formation might have an important role in the pathophysiology of bone erosions in RA patients.
- Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients-A longitudinal analysis(2017) WUNDERLICH, Carolin; OLIVIERA, Isabelle; FIGUEIREDO, Camille P.; RECH, Juergen; SCHETT, GeorgObjective: To study whether stable treatment with DMARDs affects anti-CCP2 antibody levels in patients with rheumatoid arthritis. Methods: In this longitudinal observational study 100 RA patients were followed for anti-CCP2 IgG antibody (U/L) and total IgG level (mg/dL) every 6 months for a total period of 2.5 years. All patients received stable DMARD treatment during this period. Five groups comprising each 20 patients were analyzed as follows: (1) methotrexate (MTX) alone, (2) tumor necrosis factor inhibitors (TNFi), (3) tocilizumab (TCZ), (4) rituximab (RTX), and (5) abatacept (ABA). Results: Baseline demographic and disease-specific characteristics were comparable between the 5 groups. Anti-CCP2 antibody levels did not show significant changes in patients treated with MTX (mean +/- SEM: -24.1 +/- 8.1%), TNFi (-14.0 +/- 11.1%) or TCZ (-24.3 +/- 11.3%) between baseline and the 2.5 years follow-up. In contrast, anti-CCP2 antibody levels significantly decreased during treatment with RTX (-75.6 +/- 4.4%) and ABA (-82.5 +/- 3.7%). With respect to total IgG levels, no significant changes were observed with MTX (-1.6 +/- 3.5%), TNFi (-2.5 +/- 3.4%), TCZ (-4.4 +/- 3.1%), or ABA (-2.4 +/- 3.8%) over 2.5 years. In contrast, total IgG levels significantly decreased during treatment with RTX (-22.0 +/- 3.7%). Conclusions: DMARDs targeting the adaptive immune response such as ABA and RTX significantly lowered anti-CCP2 IgG levels, while cytokine inhibitors and methotrexate had no significant effects on anti-CCP2 IgG levels. RTX is the only DMARD, which also lowers total IgG level. (C) 2017 Published by Elsevier Inc.
conferenceObject Effects of DMARD Tapering on Treatment Costs and Work Productivity in Rheumatoid Arthritis Patients- an Analysis from the Prospective Randomized Controlled Retro- Study(2016) HAGEN, Melanie; FIGUEIREDO, Camille P.; COBRA, Jayme Fogagnolo; HASCHKA, Judith; REISER, Michaela; ENGLBRECHT, Matthias; HUEBER, Axel J.; MANGER, Bernhard; KLEYER, Arnd; FINZEL, Stephanie; TONY, Hans-Peter; KLEINERT, Stefan; WENDLER, Joerg; SCHUCH, Florian; RONNEBERGER, Monika; FEUCHTENBERGER, Martin; FLECK, Martin; MANGER, Karin; OCHS, Wolfgang; SCHMITT-HAENDLE, Matthias; LORENZ, H. -M.; NUSSLEIN, H. G.; ALTEN, R.; HENES, Joerg C.; KRUGER, Klaus; SCHETT, Georg; RECH, Juergen- Does methotrexate influence COVID-19 infection? Case series and mechanistic data(2021) SCHAELTER, Fabian; DUERHOLZ, Kerstin; BUCCI, Laura; BURMESTER, Gerd; CAPORALI, Roberto; FIGUEREIDO, Camille; COBRA, Jaime Fogagnolo; MANGER, Bernhard; ZAISS, Mario M.; SCHETT, GeorgBackground To investigate whether methotrexate treatment may affect the susceptibility to infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods Clinical assessment of symptoms, SARS-CoV-2 RNA, and anti-SARS-CoV-2 IgG in an initial case series of four families and confirmatory case series of seven families, within which one family member developed coronavirus disease 19 (COVID-19) and exposed another family member receiving methotrexate treatment; experimental part with methotrexate treatment of mice and organoids followed by the assessment of mRNA and protein expression of the SARS-CoV-2 receptor angiotensin-converting enzyme (ACE)-2. Results In the initial case series, three of four women on a joint ski trip developed COVID-19, while the fourth woman, under treatment with methotrexate, remained virus-free. Two of the three diseased women infected their husbands, while the third husband treated with methotrexate remained virus-free. In addition, 7 other families were identified in a follow-up case series, in which one member developed COVID-19, while the other, receiving methotrexate, remained healthy. Experimentally, when mice were treated with methotrexate, ACE2 expression significantly decreased in the lung, in the intestinal epithelium, and in intestinal organoids. Conclusion These clinical and experimental data indicate that methotrexate has certain protective effects on SARS-CoV-2 infection via downregulating ACE2.
- Abatacept blocks anti-citrullinated protein antibody and rheumatoid factor mediated cytokine production in human macrophages in IDO-dependent manner(2018) BOZEC, Aline; LUO, Yubin; ENGDAHL, Cecilia; FIGUEIREDO, Camille; BANG, Holger; SCHETT, GeorgBackground: The anti-inflammatory effect of abatacept is most pronounced in patients with high-titer autoantibodies (including anticitrullinated protein antibodies [ACPA] and rheumatoid factor [RF]). Considering that autoantibodies trigger inflammatory cytokine production by monocytes and that abatacept binds to monocytes, influencing their functional state, we hypothesized that abatacept may effectively inhibit the production of several different cytokines by ACPA-or RF-challenged monocytes. Methods: Peripheral blood CD68(+) monocytes stimulated with macrophage colony-stimulating factor for 24 h were exposed to random immunoglobulin G alone (negative control), purified ACPA, purified RF, or lipopolysaccharide (positive control) in cell culture plates coated with citrullinated vimentin (to allow ACPA immune complex formation). Stimulations were done in the presence or absence of abatacept or tumor necrosis factor (TNF) antibody (adalimumab) with or without indoleamine 2,3-dioxygenase (IDO) inhibitor 1-methyl-D-tryptophan. Supernatants were analyzed for key proinflammatory cytokines TNF-alpha, interleukin (IL)-1 beta, IL-6, IL-8, and chemokine (C-C motif) ligand 2 (CCL2) after 24 h. Results: Exposure to ACPA or RF significantly induced the production of TNF-alpha (20-fold and 27-fold, respectively), IL-1 beta (each 4-fold), IL-6 (12-fold and 11-fold, respectively), IL-8 (43-fold and 30-fold, respectively), and CCL2 (each 4-fold) in human monocytes. Abatacept inhibited this autoantibody-mediated upregulation of cytokines, reducing TNF-a by > 75%, IL-1 beta by > 65%, IL-6 and IL-8 by > 80%, and CCL2 by > 60%. In contrast, a TNF inhibitor did not influence autoantibody-induced proinflammatory cytokine production. IDO inhibition reversed the effect of abatacept and again permitted the induction of cytokine production by ACPA and RF. Conclusions: These data show that abatacept interferes with autoantibody-mediated cytokine production by monocytes through induction of IDO. This inhibitory effect on the production of several effector cytokines in RA may explain the fast anti-inflammatory effect of abatacept as well as its preferential efficacy in patients with high-titer ACPA and RF.
- Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment(2016) RECH, Juergen; HUEBER, Axel J.; FINZEL, Stephanie; ENGLBRECHT, Matthias; HASCHKA, Judith; MANGER, Bernhard; KLEYER, Arnd; REISER, Michaela; COBRA, Jayme Fogagnolo; FIGUEIREDO, Camille; TONY, Hans-Peter; KLEINERT, Stefan; WENDLER, Joerg; SCHUCH, Florian; RONNEBERGER, Monika; FEUCHTENBERGER, Martin; FLECK, Martin; MANGER, Karin; OCHS, Wolfgang; SCHMITT-HAENDLE, Matthias; LORENZ, Hanns-Martin; NUESSLEIN, Hubert; ALTEN, Rieke; HENES, Joerg; KRUEGER, Klaus; SCHETT, GeorgObjective To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. Methods MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. Results Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). Conclusions MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. Trial registration number EudraCT 2009-015740-42.
- Methods for segmentation of rheumatoid arthritis bone erosions in high-resolution peripheral quantitative computed tomography (HR-pQCT)(2018) FIGUEIREDO, Camille P.; KLEYER, Arnd; SIMON, David; STEMMLER, Fabian; D'OLIVEIRA, Isabelle; WEISSENFELS, Anja; MUSEYKO, Oleg; FRIEDBERGER, Andreas; HUEBER, Axel J.; HASCHKA, Judith; ENGLBRECHT, Matthias; PEREIRA, Rosa M. R.; RECH, Juergen; SCHETT, Georg; ENGELKE, KlausObjective: The comparison between different techniques to quantify the 3-dimensional size of inflammatory bone erosions in rheumatoid arthritis(RA) patients. Methods: Anti-cyclic citrullinated peptide antibody(ACPA) positive RA patients received high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the metacarpophalangeal joints (MCP). Erosions were measured by three different segmentation techniques: (1) manual method with calculation by half-ellipsoid formula, (2) semi-automated modified Evaluation Script for Erosions (mESE), and (3) semi-automated Medical Image Analysis Framework (MIAF) software. Bland & Altman plots were used to describe agreement between methods. Furthermore, shape of erosions was classified as regular or irregular and then compared to the sphericity obtained by MIAF. Results: A total of 76 erosions from 65 RA patients (46 females/19 males), median age 57 years, median disease duration 6.1 years and median disease activity score 28 of 2.8 units were analyzed. While mESE and MIAF showed good agreement in the measurement of erosion size, the manual method with calculation by half-ellipsoid formula underestimated erosions size, particularly with larger erosions. Accurate segmentation is particularly important in larger erosions, which are irregularly shaped. In all three segmentation techniques irregular erosions were larger in size than regular erosions (MIAF: 19.7 vs. 3.4 mm(3); mESE: 15.5 vs. 2.3 mm(3); manual = 7.2 vs. 1.52 mm(3); all p < 0.001). In accordance, sphericity of erosions measured by MIAF significantly decreased with their size (p < 0.001). Conclusion: MIAF and mESE allow segmentation of inflammatory bone erosions in RA patients with excellent inter reader reliability. They allow calculating erosion volume independent of erosion shape and therefore provide an attractive tool to quantify structural damage in individual joints of RA patients.