Monocyte populations as markers of response to adalimumab plus MTX in rheumatoid arthritis

Chara, L.E.; Sánchez-Atrio, Ana; Pérez, Ana; Cuende, Eduardo; Albarrán, Fernando Vicente; Turrión, Ana; Chevarría, Julio; Sánchez, Miguel; Monserrat, Jorge; Hera, Alberto De La; Prieto, Alfredo; Sanz, Igñacio; Díaz, David; Álvarez‐Mon, Melchor

doi:10.1186/ar3928

Cited by 48 publications

(39 citation statements)

References 37 publications

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“…The expression of CD18 was stronger on CD163 + than CD163 - monocytes ( P <0.001). Confirming the finding from previous studies of arthritis [7-9], there were a non-significant, greater proportion of intermediate monocytes among all monocytes in HLA-B27-negative SpA patients compared with HCs (Figure 6C). A positive correlation was observed between the proportion of non-classic (Figure 7A) and intermediate (Figure 7B) monocytes among all CD14 + monocytes and the concentration of sCD18 in the PBMC culture supernatants, whereas a negative correlation was found for the proportion of classic monocytes (Figure 7C).…”

Section: Resultssupporting

confidence: 91%

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

et al. 2014

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IntroductionSpondyloarthritis (SpA) comprises a group of diseases often associated with HLA-B27 and characterized by inflammation of the entheses and joints of the axial skeleton. The inflammatory process in SpA is presumably driven by innate immune cells but is still poorly understood. Thus, new tools for monitoring and treating inflammation are needed. The family of CD18 integrins is pivotal in guiding leukocytes to sites of inflammation, and CD18 hypomorphic mice develop a disease resembling SpA. Previously, we demonstrated that altered soluble CD18 (sCD18) complexes in the blood and synovial fluid of patients with arthritis have anti-inflammatory functions. Here, we study the mechanisms for these alterations and their association with SpA disease activity.MethodsPlasma levels of sCD18 in a study population with 84 patients with SpA and matched healthy controls were analyzed with a time-resolved immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synoviocytes (FLSs) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMCs) was studied with flow cytometry and TRIFMA.ResultsPlasma levels of sCD18 were decreased in patients with SpA compared with healthy volunteers (P <0.001), and the lowest levels were in the HLA-B27-positive subgroup (P <0.05). In a multiple regression model, the sCD18 levels exhibited an inverse correlation with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (P <0.05), the level of morning stiffness (P <0.05), the Bath Ankylosing Spondilitis Metrology Index (P <0.05), the physician global assessment score (P <0.01), and the sacroiliac magnetic resonance imaging activity score (P <0.05). The mechanisms for these changes could be simulated in vitro. First, sCD18 in plasma adhered to inflammation-induced intercellular adhesion molecule 1 (ICAM-1) on endothelial cells and FLS, indicating increased consumption. Second, CD18 shedding from SpA PBMCs correlated inversely with the BASDAI (P <0.05), suggesting insufficient generation. CD18 was shed primarily from intermediate CD14++ CD16+ monocytes, supporting the view that alterations in innate immunity can regulate the inflammatory processes in SpA.ConclusionsTaken together, the failure of patients with SpA to maintain adequate sCD18 levels may reflect insufficient CD18 shedding from monocytes to counterbalance the capture of sCD18 complexes to inflammation-induced ICAM-1. This could increase the availability of ICAM-1 molecules on the endothelium and in the synovium, facilitating leukocyte migration to the entheses and joints and aggregating disease activity.

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Section: Resultssupporting

confidence: 91%

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

et al. 2014

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“…Neutrophil granule genes exhibited higher expression in nonresponders than in responders before treatment with anti‐TNF agents . Monocyte numbers have been reported to be higher in nonresponders than in responders after 3 or 6 months of anti‐TNF treatment . These results suggest enhanced activity of alternative immune pathways in anti‐TNF‐IR patients that may be targeted for clinical improvement.…”

Section: Discussionmentioning

confidence: 95%

Pharmacodynamic biomarkers and differential effects of TNF‐ and GM‐CSF‐targeting biologics in rheumatoid arthritis

Guo

Wang

Godwood³

et al. 2018

Int J of Rheum Dis

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Aim The aim of our study was to identify pharmacodynamic biomarkers and assess differential effects of tumor necrosis factor (TNF)‐ and non‐TNF‐targeting agents on rheumatoid arthritis (RA) patients with an inadequate response to anti‐TNF agents (anti‐TNF‐IR) in comparison with biologic‐naïve patients. Methods EARTH EXPLORER 2, a phase IIb trial, evaluated golimumab, an anti‐TNF antibody, and mavrilimumab, an granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) receptor antibody, in disease‐modifying antirheumatic drug (DMARD)‐IR and anti‐TNF‐IR patients. Our current study assessed peripheral protein markers and gene expression levels in association with clinical response post‐treatment in two disease strata. Results Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti‐TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including interleukin (IL)‐6, C‐reactive protein, IL2RA, and matrix metalloproteinase 1, in DMARD‐IR patients. Golimumab‐induced early changes rapidly returned toward baseline concentrations in anti‐TNF‐IR patients, whereas mavrilimumab‐induced changes were maintained through to day 169. RNA sequencing demonstrated gene expression changes at day 169 after administration of mavrilimumab but not golimumab in anti‐TNF‐IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL‐6 change and subsequent clinical responses to golimumab in anti‐TNF‐IR patients. Conclusion Our results revealed golimumab‐ and mavrilimumab‐specific pharmacodynamic biomarkers, and demonstrated differential biomarker‐treatment relationships in anti‐TNF‐IR and DMARD‐IR patients, respectively. Early IL‐6 change after anti‐TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti‐TNF‐IR patients.

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“…The main findings of this study are that patients with IIM have an expansion of circulating intermediate monocytes and that their monocytes subsets have a differential expression of TLR4 and TLR2, which correlate with serum IL-6, as well as with distinctive clinical features. Previously, it was shown that anti-TNF therapy is able to reduce the expression of TLRs in monocytes from patients with rheumatoid arthritis (RA) and spondylarthopathy [27,28]. Nevertheless, most studies have demonstrated that immunosuppressive therapy does not have an effect in the proportion of monocyte subsets, as shown in patients with RA under methotrexate treatment [29] and in patients with solid organ transplantation [30].…”

Section: Discussionmentioning

confidence: 99%

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

et al. 2020

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Background: Monocytes and toll-like receptors (TLR) have been found in the inflammatory infiltrate of muscle biopsies in patients with idiopathic inflammatory myopathies (IIM), suggesting an important role of these cells in the pathogenesis of myositis. The monocyte subsets, their TLR expression in peripheral blood and their relationship with the clinical characteristics of patients with IIM has not been addressed. Methods:We recruited 45 patients with IIM diagnosis and 15 age and sex-adjusted healthy controls. We assessed the disease activity and damage, performed a nailfold capillaroscopy and registered the cardio-pulmonary parameters from the medical charts. Monocyte subsets, their expression of TLR2 and TLR4 and the serum Th1/Th2/Th17 cytokines levels were evaluated by flow cytometry. We expressed quantitative variables as medians and interquartile ranges (IQR) or minimum and maximum (min-max). Differences between groups were assessed with Mann-Whitney U and the Kruskal-Wallis tests. Correlation between quantitative variables was assessed with Spearman Rho.Results: Twenty-nine patients were women (64.4%) and 32 (71.1%) had dermatomyositis. In comparison to healthy controls, patients with active IIM had a higher percentage of intermediate monocytes and lower amounts of classical monocytes. Patients with IIM had a higher expression of TLR4 in all their monocyte subsets, regardless of disease activity and prednisone treatment. Serum IL-6 correlated with the TLR2 expression in every monocyte subset and the expression of TLR2 in intermediate monocytes was higher among patients with dysphagia. Subjects with nailfold capillaroscopy abnormalities had a higher amount of TLR2+ classical and non-classical monocytes and those with interstitial lung disease (ILD) had a higher percentage of TLR4+ non-classical monocytes. The classical and intermediate monocytes from patients with anti Mi2 antibodies had a higher expression of TLR4. The percentage of intermediate monocytes and the expression of TLR4 in all monocyte subsets showed a good diagnostic capacity in patients with IIM. Conclusion:Patients with IIM have a differential pool of monocyte subsets with an enhanced expression of TLR2 and TLR4, which correlates with disease activity and distinctive clinical features including dysphagia, ILD, vasculopathy, and pro-inflammatory cytokines. These immunological features might be useful as a potential diagnostic tool as well as novel disease activity biomarkers in IIM.

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Monocyte populations as markers of response to adalimumab plus MTX in rheumatoid arthritis

Cited by 48 publications

References 37 publications

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis

Pharmacodynamic biomarkers and differential effects of TNF‐ and GM‐CSF‐targeting biologics in rheumatoid arthritis

TLR expression in peripheral monocyte subsets of patients with idiopathic inflammatory myopathies: association with clinical and immunological features

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