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OBJECTIVE: Rheumatoid Arthritis (RA) often exhibits suboptimal treatment response despite early diagnosis and treatment. This study aimed to analyze Early Rheumatoid Arthritis (ERA) synovial biopsies through histology and immunohistochemistry (IHC) to identify predictive factors for treatment response to Methotrexate (MTX). METHODS: 140 ERA patients from the UCLouvain Arthritis Cohort underwent synovial biopsy and were monitored after initiating Disease-Modifying Antirheumatic Drug (DMARD) therapy. Histological features [Synovial Hyperplasia, Fibrinoid Necrosis (FN), Hypervascularization and Inflammatory Infiltrate] and IHC (CD3, CD20, CD138, CD68) were each semi-quantitatively assessed on a 0-3 scale with 7 levels. RESULTS: A strong association was observed between synovial CD68 and Fibrinoid Necrosis scores [r = 0.44 (0.27 - 0.56); p < 0.0001]. CD68 correlated with C-Reactive Protein (CRP), DAS28, SDAI and CDAI. Fibrinoid Necrosis score correlated with CRP and DAS28. Patients were then categorized as CD68NecrosisHIGH (CD68 + Necrosis ≥ 3) and CD68NecrosisLOW (CD68 + Necrosis < 3). CD68NecrosisHIGH exhibited higher pre-treatment disease activity [5.48 (1.6) versus 4.8 (1.7); p = 0.03] and a greater fall in DAS28 [1.99 (2.06) versus 1.1 (2.27), p = 0.03], SDAI [21.45 (IQR 23.3) versus 11.65 (IQR 17.5); p = 0.003] and CDAI [16 [14.9] versus 10.5 (20.1), p = 0.04]. CD68NecrosisHIGH patients had a higher EULAR Moderate/Good Response rate. CD68Necrosis score was incorporated into a probability matrix model together with clinical features (SJC44 and DAS28) to predict achieving a Moderate/Good EULAR Response Criteria at 3 months with a good performance (AUC 0.724). CONCLUSION: FN and CD68 + in ERA synovial biopsies identify patients with higher disease activity and predict a better treatment response at three months. A model including synovial CD68 and fibrinoid necrosis with baseline clinical features predicts EULAR response at 3 months.
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Antirreumáticos , Artrite Reumatoide , Metotrexato , Necrose , Membrana Sinovial , Humanos , Metotrexato/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Feminino , Masculino , Pessoa de Meia-Idade , Membrana Sinovial/patologia , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/metabolismo , Antirreumáticos/uso terapêutico , Idoso , Estudos de Coortes , Adulto , Resultado do Tratamento , Imuno-HistoquímicaRESUMO
OBJECTIVE: The objective is to characterize transcriptomic profiles and immune cell composition and distribution in juvenile idiopathic arthritis (JIA) synovial biopsies, assess for associations of these features with clinical parameters, and compare JIA and rheumatoid arthritis (RA) synovial features. METHODS: RNA sequencing (RNASeq) was performed on 24 samples, with pathway analysis and inference of relative abundance of immune cell subsets based on gene expression data. Two multiplex fluorescence immunohistochemistry (IHC) panels were performed on 28 samples (including 13 on which RNASeq was performed), staining for CD206- classical and CD206+ nonclassical macrophages, and CD8+ and CD4+ T and B lymphocytes. Data were compared to a published series of early RA synovial biopsies. RESULTS: Pathway analysis of the most variably expressed genes (n = 339) identified a B and plasma cell signature as the main driver of heterogeneity in JIA synovia, with strong overlap between JIA and RA synovitis. Multiplex IHC confirmed heterogeneity of immune cell infiltration. M1-like macrophage-rich synovial lining was associated with greater lining hypertrophy and higher (CD45+) pan-immune cell and CD8+ T cell infiltration. CONCLUSION: Our study indicates significant similarities between JIA and RA synovitis. Similar to RA, JIA synovia may be broadly categorized into two groups: (1) those with an inflammatory/adaptive immune transcriptomic signature, M1-like macrophage and CD8+ T cell infiltration, and thicker, M1-like macrophage-rich synovial lining, and (2) those with an M2-like macrophage transcriptomic signature, greater M2/M1-like macrophage ratios, and thinner, M2-like macrophage-rich synovial lining. Synovial features were not significantly associated with clinical parameters, likely because of group size and heterogeneity.
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BACKGROUND: Neoadjuvant chemotherapy (NAC) is the standard of care for patients with early-stage triple negative breast cancers (TNBC). However, more than half of TNBC patients do not achieve a pathological complete response (pCR) after NAC, and residual cancer burden (RCB) is associated with dismal long-term prognosis. Understanding the mechanisms underlying differential treatment outcomes is therefore critical to limit RCB and improve NAC efficiency. METHODS: Human TNBC cell lines and patient-derived organoids were used in combination with real-time metabolic assays to evaluate the effect of NAC (paclitaxel and epirubicin) on tumor cell metabolism, in particular glycolysis. Diagnostic biopsies (pre-NAC) from patients with early TNBC were analyzed by bulk RNA-sequencing to evaluate the predictive value of a glycolysis-related gene signature. RESULTS: Paclitaxel induced a consistent metabolic switch to glycolysis, correlated with a reduced mitochondrial oxidative metabolism, in TNBC cells. In pre-NAC diagnostic biopsies from TNBC patients, glycolysis was found to be upregulated in non-responders. Furthermore, glycolysis inhibition greatly improved response to NAC in TNBC organoid models. CONCLUSIONS: Our study pinpoints a metabolic adaptation to glycolysis as a mechanism driving resistance to NAC in TNBC. Our data pave the way for the use of glycolysis-related genes as predictive biomarkers for NAC response, as well as the development of inhibitors to overcome this glycolysis-driven resistance to NAC in human TNBC patients.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia , Terapia Neoadjuvante , Prognóstico , Resultado do Tratamento , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
OBJECTIVES: Patients with HER2-positive invasive breast cancer that is node-positive and/or larger than 3 cm are generally treated with neoadjuvant chemotherapy (NAC). We aimed to identify predictive markers for pathological complete response (pCR) after NAC in HER2-positive breast carcinoma. METHODS: Hematoxylin/eosin-stained slides of 43 HER2-positive breast carcinoma biopsies were histopathologically reviewed. Immunohistochemistry (IHC) was performed on pre-NAC biopsies, comprising HER2, estrogen receptor (ER), progesterone receptor (PR), Ki-67, epidermal growth factor receptor (EGFR), mucin-4 (MUC4), p53 and p63. Dual-probe HER2 in situ hybridization (ISH) was performed to study the mean HER2 and CEP17 copy numbers. ISH and IHC data were retrospectively collected for a validation cohort, comprising 33 patients. RESULTS: Younger age at diagnosis, 3+ HER2 IHC scores, high mean HER2 copy numbers and high mean HER2/CEP17 ratios were significantly associated with an increased chance of achieving a pCR, and the latter two associations were confirmed in the validation cohort. No other immunohistochemical or histopathological markers were associated with pCR. CONCLUSIONS: This retrospective study of two community-based NAC-treated HER2-positive breast cancer patient cohorts identified high mean HER2 copy numbers as a strong predictor for pCR. Further studies on larger cohorts are required to determine a precise cut-point for this predictive marker.
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Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Estudos Retrospectivos , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/análise , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptores de Progesterona/metabolismoRESUMO
OBJECTIVES: Transcriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups. METHODS: RNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections. RESULTS: PCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers. CONCLUSION: In this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.
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Artrite Reumatoide , Sinovite , Humanos , Transcriptoma , Sinovite/patologia , Membrana Sinovial/metabolismo , InflamaçãoRESUMO
The assessment of PD-L1 expression in TNBC is a prerequisite for selecting patients for immunotherapy. The accurate assessment of PD-L1 is pivotal, but the data suggest poor reproducibility. A total of 100 core biopsies were stained using the VENTANA Roche SP142 assay, scanned and scored by 12 pathologists. Absolute agreement, consensus scoring, Cohen's Kappa and intraclass correlation coefficient (ICC) were assessed. A second scoring round after a washout period to assess intra-observer agreement was carried out. Absolute agreement occurred in 52% and 60% of cases in the first and second round, respectively. Overall agreement was substantial (Kappa 0.654-0.655) and higher for expert pathologists, particularly on scoring TNBC (6.00 vs. 0.568 in the second round). The intra-observer agreement was substantial to almost perfect (Kappa: 0.667-0.956), regardless of PD-L1 scoring experience. The expert scorers were more concordant in evaluating staining percentage compared with the non-experienced scorers (R2 = 0.920 vs. 0.890). Discordance predominantly occurred in low-expressing cases around the 1% value. Some technical reasons contributed to the discordance. The study shows reassuringly strong inter- and intra-observer concordance among pathologists in PD-L1 scoring. A proportion of low-expressors remain challenging to assess, and these would benefit from addressing the technical issues, testing a different sample and/or referring for expert opinions.
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The human breast, as mentioned by Gudjonsson and co-authors [...].
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Silicone breast implants are frequently used for breast augmentation for cosmetic purposes, as well as for breast reconstruction after prophylactic or therapeutic mastectomy. Silicone lymphadenopathy is a well-known complication of silicone breast implants. Silicone droplets are present in the breast tissue through 'silicone bleeding' of the implant or because of implant rupture. These silicone particles can migrate from the breast to the regional lymph nodes. Silicone lymphadenopathy is caused by a substantial foreign body reaction against these silicone particles, and is frequently associated with asteroid body-containing multinucleated giant cells. Similar multinucleated giant cells are often observed in the capsule surrounding the silicone breast implant, and the number of associated asteroid bodies is highly variable. Here, we discuss a series of twelve women with breast implant-related asteroid bodies in their lymph nodes and/or breast tissue. This pictorial essay illustrates that the presence of asteroid bodies in a lymph node does not necessarily suggests a diagnosis of sarcoidosis. Clinical information about the patient having (or having had) silicone breast implants is often lacking. The encounter of asteroid body-containing giant cells in lymph node cytology, biopsies or resections should therefore lead to reflex clinical-pathological correlation, before establishing a final diagnosis.
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Implantes de Mama , Neoplasias da Mama , Linfadenopatia , Doenças Linfáticas , Sarcoidose , Feminino , Humanos , Implantes de Mama/efeitos adversos , Géis de Silicone/efeitos adversos , Doenças Linfáticas/diagnóstico , Doenças Linfáticas/etiologia , Doenças Linfáticas/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/cirurgia , Neoplasias da Mama/complicações , Mastectomia , Linfadenopatia/etiologia , Linfadenopatia/complicações , Sarcoidose/diagnóstico , Sarcoidose/complicaçõesRESUMO
Pathological complete response (pCR) after neoadjuvant chemotherapy in patients with early breast cancer is correlated with better survival. Meanwhile, an expanding arsenal of post-neoadjuvant treatment strategies have proven beneficial in the absence of pCR, leading to an increased use of neoadjuvant systemic therapy in patients with early breast cancer and the search for predictive biomarkers of response. The better prediction of response to neoadjuvant chemotherapy could enable the escalation or de-escalation of neoadjuvant treatment strategies, with the ultimate goal of improving the clinical management of early breast cancer. Clinico-pathological prognostic factors are currently used to estimate the potential benefit of neoadjuvant systemic treatment but are not accurate enough to allow for personalized response prediction. Other factors have recently been proposed but are not yet implementable in daily clinical practice or remain of limited utility due to the intertumoral heterogeneity of breast cancer. In this review, we describe the current knowledge about predictive factors for response to neoadjuvant chemotherapy in breast cancer patients and highlight the future perspectives that could lead to the better prediction of response, focusing on the current biomarkers used for clinical decision making and the different gene signatures that have recently been proposed for patient stratification and the prediction of response to therapies. We also discuss the intratumoral phenotypic heterogeneity in breast cancers as well as the emerging techniques and relevant pre-clinical models that could integrate this biological factor currently limiting the reliable prediction of response to neoadjuvant systemic therapy.
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BACKGROUND: Late distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC is still only partially understood. METHODS: We retrospectively identified 38 ILC patients from the tissue banks of six European institutions. DNA extracted from patient matched primary and metastatic FFPE tissue blocks was whole genome sequenced to compute somatic copy number aberrations. This, in turn, was used to infer the evolutionary history of these patients. FINDINGS: The data show different metastatic seeding patterns, with both an early and late divergence of the metastatic lineage observed in ILC. Additionally, cascading dissemination from a metastatic precursor was a dominant rule. Alterations in key cancer driver genes, such as TP53 or CCND1, were acquired early while additional aberrations were present only in the metastatic branch. In about 30% of the patients, the metastatic lineage harboured less aberrations than the primary tumour suggesting a period of tumour dormancy or prolonged adaptation at the distant site. This phenomenon was mostly observed in tumours from de novo metastatic patients. INTERPRETATION: Our results provide insights into ILC evolution and offer potential paths for optimised ILC care. FUNDING: This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF) and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS).
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Neoplasias da Mama , Carcinoma Lobular , Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Carcinoma Lobular/genética , Carcinoma Lobular/patologia , Carcinoma Lobular/secundário , Feminino , Humanos , Filogenia , Estudos RetrospectivosRESUMO
The occurrence of a pathological fracture in children requires a rigorous diagnostic approach in order to establish the etiology and to develop a precise therapeutic strategy. Several causes are associated with these fractures, the most frequent being benign tumors in children in developed countries and chronic osteomyelitis in developing countries. More rarely, malignant tumors must however always be considered. The differential diagnosis on imaging may be difficult to establish between bone tumors and chronic infection. Surgical biopsy is therefore often performed to establish the precise origin of the fracture. We report the case of an adamantinoma (osteofibrous dysplasia-like) of the fibula in a 7-year-old child, discovered during the management of a pathologic fracture. The presumed diagnosis before biopsy was chronic osteomyelitis. A 14-cm-resection of the affected fibula was performed with good functional result. Differential diagnosis between adamantinoma, osteofibrous dysplasia and osteofibrous dysplasia-like adamantinoma remains very challenging.
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INTRODUCTION: The ETV6::NTRK3 fusion is the most common gene alteration in infantile fibrosarcoma, a soft tissue tumor affecting patients under two years of age. Less frequently, these tumors harbor fusions of genes encoding other kinases, such as BRAF, which activates MEK in the mitogen-activated protein kinase pathway. The identification and characterization of these oncogenes are crucial to facilitate diagnosis, validate new treatments, and better understand the pathophysiology of these neoplasms. METHODS: Herein, we analyzed an ETV6::NTRK3-negative infantile fibrosarcoma from a 5-day-old patient by RNA-sequencing to identify new fusion transcripts. Functional exploration of the fusion of interest was performed by in vitro assays to study its activity, oncogenicity, and sensitivity to the MEK inhibitor trametinib. RESULTS: We identified a novel fusion involving the PHIP and BRAF genes. The corresponding fusion protein constitutively activated the mitogen-activated protein kinase pathway, resulting in fibroblast transformation. Treatment of transfected cells with trametinib effectively inhibited signaling by PHIP::BRAF. CONCLUSION: PHIP::BRAF is a novel fusion oncogene that can be targeted by trametinib in infantile fibrosarcoma.
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Fibrossarcoma , Peptídeos e Proteínas de Sinalização Intracelular , Neoplasias Musculares , Proteínas de Fusão Oncogênica , Proteínas Proto-Oncogênicas B-raf , Fibrossarcoma/genética , Humanos , Recém-Nascido , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Neoplasias Musculares/genética , Proteínas de Fusão Oncogênica/genética , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
Epidemiological studies suggest that around 10% of breast cancers are due to hereditary predisposition. The risk of cancer is exponentially increased in patients harboring BRCA1 or BRCA2 mutations. Cumulative breast cancer risk by age 80 is estimated to 72% for BRCA1 mutation carriers and 69% for BRCA2. The cumulative risk estimates for developing ovarian cancer by age 80 are 44% for BRCA1 mutation carriers and 17% for BRCA2. We present here the case of a 59-year-old woman who developed a left breast cancer in 2014 treated by conservative surgery, radiotherapy, and endocrine therapy with letrozole. The diagnosis of BRCA1 mutation was performed in 2015. In 2018, the patient was referred to our institution for treatment of an aggressive angiosarcoma developed in the same breast. She had undergone radical hysterectomy by the age of 49 years for a benign uterine pathology. In 2020, she developed a tumor in the gastric wall; histological analysis confirmed a serous papillary carcinoma of ovarian origin. She was treated - after gastrectomy and lymphadenectomy - with 6 courses of carboplatin and paclitaxel followed by olaparib therapy. In 2021, she suffered from a chest recurrence of high grade angiosarcoma. New resection with free margins was performed. We discuss the link between angiosarcomas and BRCA mutations, the therapeutic options for angiosarcoma and ovarian cancer of extra ovarian origin and the follow-up modalities.
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Bone tissue can be involved by primitive or metastatic tumors and requires a specific processing both at the department of pathology and during multidisciplinary meetings. The development of fine-needle percutaneous biopsies and of molecular techniques in bone tumor pathology requires a specific management. Moreover, decalcification of samples is crucial but can be deleterious if not controlled or not appropriate. The aim of this review is to provide recommendations for management and decalcification of bone tumor samples.
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Neoplasias Ósseas , Neoplasias Ósseas/secundário , Neoplasias Ósseas/terapia , Osso e Ossos , Técnica de Descalcificação/métodos , Humanos , Imuno-HistoquímicaRESUMO
Transgender women experience gender dysphoria due to a gender assignment at birth that is incongruent with their gender identity. Transgender people undergo different surgical procedures and receive sex steroids hormones to reduce psychological distress and to induce and maintain desired physical changes. These persons on feminizing hormones represent a unique population to study the hormonal effects on breast development, to evaluate the risk of breast cancer and perhaps to better understand the precise role played by different hormonal components. In MTF (male to female) patients, hormonal treatment usually consists of antiandrogens and estrogens. Exogenous hormones induce breast development with the formation of ducts and lobules and an increase in the deposition of fat. A search of the existing literature dedicated to hormone regimens for MTF patients, their impact on breast tissue (incidence and type of breast lesions) and breast cancer risk provided the available information for this review. The evaluation of breast cancer risk is currently complicated by the heterogeneity of administered treatments and a lack of long-term follow-up in the great majority of studies. Large studies with longer follow-up are required to better evaluate the breast cancer risk and to understand the precise mechanisms on breast development of each exogenous hormone.
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OBJECTIVES: Because a significant fraction of patients with lupus nephritis (LN) develops renal impairment, there is a need to better understand the mechanisms underlying disease progression. Here, we assessed for cellular senescence in the LN kidney, and its association with disease severity and outcome. METHODS: We enumerated the number of cells positive for p16INK4a protein, a marker of cellular senescence, by immunohistochemistry followed by digital quantification, on renal biopsies from 40 patients with active LN. We tested for an association of p16INK4a with renal fibrosis, CD8+ T cell infiltration, systemic disease and renal function at baseline and at 5 years. RESULTS: The presence of p16INK4a-positive cells was significantly associated with lower estimated glomerular filtration rate at baseline and 5 years post-treatment, independently of patient demographics and systemic disease parameters. It was also associated with higher baseline renal fibrosis and CD8+ T cell infiltration. Interestingly, we observed marked spatial co-distribution of glomerular p16INK4a-positive cells with CD8+ T cells. CONCLUSION: We demonstrate, for the first time, that LN biopsies characterised by renal impairment display increased p16INK4a-positive cells, associated with higher fibrosis and CD8+ T cell infiltration. Cellular senescence may represent a kidney-intrinsic disease mechanism and potentially, a novel therapeutic target in LN.
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Inibidor p16 de Quinase Dependente de Ciclina , Nefrite Lúpica , Linfócitos T CD8-Positivos , Senescência Celular , Humanos , Rim/fisiologiaRESUMO
Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing's sarcoma resection surgery. Chronic infection by Clostridium hathewayi, Proteus mirabilis and Finegoldia magna was worsened by methicillin-susceptible Staphylococcus aureus exhibiting an inducible Macrolides-Lincosamides-Streptogramin B resistance phenotype (iMLSB). After failure of conventional conservative treatment, combination of in situ anti-S. aureus PT with surgical debridement and intravenous antibiotic therapy led to marked clinical and microbiological improvement, yet failed to prevent a recurrence of infection on the midterm. This eventually led to surgical graft replacement. Multiple factors can explain this midterm failure, among which incomplete coverage of the polymicrobial infection by PT. Indeed, no phage therapy against C. hathewayi, P. mirabilis or F. magna could be administered. Phage-antibiotic interactions were investigated using OmniLog® technology. Our results suggest that phage-antibiotic interactions should not be considered "unconditionally synergistic", and should be assessed on a case-by-case basis. Specific pharmacodynamics of phages and antibiotics might explain these differences. More than two years after final graft replacement, the patient remains cured of her sarcoma and no further infections occurred.
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Aloenxertos/microbiologia , Antibacterianos/farmacologia , Osso e Ossos/microbiologia , Coinfecção/terapia , Terapia por Fagos/métodos , Infecções Estafilocócicas/terapia , Fagos de Staphylococcus/fisiologia , Staphylococcus aureus/efeitos dos fármacos , Aloenxertos/efeitos dos fármacos , Biofilmes , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/patologia , Criança , Interações Medicamentosas , Feminino , Humanos , Sarcoma de Ewing/tratamento farmacológico , Infecções Estafilocócicas/diagnósticoRESUMO
Objectives: Our goal was to assess for the histological and transcriptomic effects of abatacept on RA synovia, and to compare them with previously published data from four other DMARDs: tocilizumab, rituximab, methotrexate, and adalimumab. Methods: Synovial tissue was obtained using ultrasound-guided biopsy from affected joints of 14 patients, before and 16 weeks after treatment with subcutaneous abatacept 125 mg weekly. Paraffin-sections were stained and scored for CD3+, CD20+, and CD68+ cell infiltration. Transcriptional profiling was performed using GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix) and analyzed on Genespring GX (Agilent). Pathway analyses were performed on Genespring GX, Metascape, and EnrichR. Results: Gene expression analysis identified 304 transcripts modulated by abatacept in synovial tissue. Downregulated genes were significantly enriched for immune processes, strongly overlapping with our findings on other therapies. Data were pooled across these studies, revealing that genes downregulated by DMARDs are significantly enriched for both T-cell and myeloid leukocyte activation pathways. Interestingly, DMARDs seem to have coordinate effects on the two pathways, with a stronger impact in good responders to therapy as compared to moderate and non-responders. Conclusion: We provide evidence that the effects of five DMARDs on the RA synovium culminate in the same pathways. This confirms previous studies suggesting the existence of common mediators downstream of DMARDs, independent of their primary targets.