Associations of ultrasound-based inflammation patterns with peripheral innate lymphoid cell populations, serum cytokine/chemokines, and treatment response to methotrexate in rheumatoid arthritis and spondyloarthritis

Abstract Background: We aimed to clarify the associations of musculoskeletal inflammation patterns with peripheral blood innate lymphoid cell (ILC) populations, serum cytokine/chemokines, and treatment response to methotrexate in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).Methods: We enrolled patients with either RA or SpA who had peripheral symptoms and performed comprehensive ultrasound to evaluate power Doppler signals for synovitis (52 joint regions), tenosynovitis (20 tendons), and enthesitis (44 sites). We performed clustering analysis using unsupervised random forest based on the multi-axis ultrasound information and classified the patients into groups. We identified and counted ILC1-3 populations in the peripheral blood by flow cytometry and also measured the serum levels of 20 cytokine/chemokines. We also determined the American College of Rheumatology 20% improvement (ACR20) response at 3 months in 38 patients who initiated treatment with methotrexate after baseline assessment. Results: We enrolled a total of 100 patients with RA (n=66) or SpA (n=34). Synovitis was more prevalent and severer in RA than in SpA, whereas tenosynovitis and enthesitis were comparable between RA and SpA. Patients were classified into two groups which represented synovitis-dominant and synovitis-nondominant inflammation patterns, respectively. While peripheral ILC counts were not significantly different between RA and SpA, they were significantly higher in the synovitis-nondominant group than in the synovitis-dominant group (ILC1-3 p=0.0007, p=0.0061, p=0.0002, respectively). On the other hand, clustering of patients based on serum cytokine/chemokines did not clearly correspond either to clinical diagnoses or to synovitis-dominant/nondominant patterns. The synovitis-nondominant pattern was the factor that predicted no clinical response to methotrexate most significantly (p=0.0065).Conclusions: Ultrasound-detected musculoskeletal inflammation is clustered into synovitis-dominant and nondominant patterns. These patterns are associated with peripheral ILC counts and could predict treatment response to methotrexate. These data suggest that ultrasound-based inflammation patterns can be utilized to establish more individualized treatment for both RA and SpA. Trial registration: The study has been registered in UMIN Clinical Trial Registry (UMIN ID: 000033797, date of registration: 18th of August, 2018).

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Associations of ultrasound-based inflammation patterns with peripheral innate lymphoid cell populations, serum cytokines/chemokines, and treatment response to methotrexate in rheumatoid arthritis and spondyloarthritis

PLoS ONE ◽

10.1371/journal.pone.0252116 ◽

2021 ◽

Vol 16 (5) ◽

pp. e0252116

Author(s):

Manami Kato ◽

Kei Ikeda ◽

Takahiro Sugiyama ◽

Shigeru Tanaka ◽

Kazuma Iida ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Treatment Response ◽

Peripheral Blood ◽

Lymphoid Cell ◽

Power Doppler ◽

Serum Levels ◽

Dominant Group ◽

Innate Lymphoid Cell ◽

Acr20 Response ◽

Serum Cytokines

Objectives We aimed to explore the associations of musculoskeletal inflammation patterns with peripheral blood innate lymphoid cell (ILC) populations, serum cytokines/chemokines, and treatment response to methotrexate in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). Methods We enrolled 100 patients with either RA or SpA and performed ultrasound to evaluate power Doppler signals for synovitis (52 joint regions), tenosynovitis (20 tendons), and enthesitis (44 sites). We performed clustering analysis using unsupervised random forest based on the multi-axis ultrasound information and classified the patients into groups. We identified and counted ILC1-3 populations in the peripheral blood by flow cytometry and also measured the serum levels of 20 cytokines/chemokines. We also determined ACR20 response at 3 months in 38 patients who began treatment with methotrexate after study assessment. Results Synovitis was more prevalent and severe in RA than in SpA, whereas tenosynovitis and enthesitis were comparable between RA and SpA. Patients were classified into two groups which represented synovitis-dominant and synovitis-nondominant inflammation patterns. While peripheral ILC counts were not significantly different between RA and SpA, they were significantly higher in the synovitis-nondominant group than in the synovitis-dominant group (ILC1-3: p = 0.0007, p = 0.0061, and p = 0.0002, respectively). On the other hand, clustering of patients based on serum cytokines/chemokines did not clearly correspond either to clinical diagnoses or to synovitis-dominant/nondominant patterns. The synovitis-dominant pattern was the most significant factor that predicted clinical response to methotrexate (p = 0.0065). Conclusions Musculoskeletal inflammation patterns determined by ultrasound are associated with peripheral ILC counts and could predict treatment response to methotrexate.

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Associations of ultrasound-based inflammation patterns with peripheral innate lymphoid cell populations, serum cytokine/chemokines, and treatment response to methotrexate in rheumatoid arthritis and spondyloarthritis

10.21203/rs.3.rs-105953/v2 ◽

2021 ◽

Keyword(s):

Rheumatoid Arthritis ◽

Treatment Response ◽

Lymphoid Cell ◽

Cell Populations ◽

Serum Cytokine ◽

Innate Lymphoid Cell

Abstract The authors have requested that this preprint be withdrawn due to erroneous posting.

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Tofacitinib Suppresses Several JAK-STAT Pathways in Rheumatoid Arthritis In Vivo and Baseline Signaling Profile Associates With Treatment Response

Frontiers in Immunology ◽

10.3389/fimmu.2021.738481 ◽

2021 ◽

Vol 12 ◽

Author(s):

Maaria Palmroth ◽

Krista Kuuliala ◽

Ritva Peltomaa ◽

Anniina Virtanen ◽

Antti Kuuliala ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

Treatment Response ◽

Peripheral Blood ◽

Janus Kinase ◽

Cytokine Signaling ◽

Stat3 Phosphorylation ◽

Stat Pathway

ObjectiveCurrent knowledge on the actions of tofacitinib on cytokine signaling pathways in rheumatoid arthritis (RA) is based on in vitro studies. Our study is the first to examine the effects of tofacitinib treatment on Janus kinase (JAK) - signal transducer and activator of transcription (STAT) pathways in vivo in patients with RA.MethodsSixteen patients with active RA, despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), received tofacitinib 5 mg twice daily for three months. Levels of constitutive and cytokine-induced phosphorylated STATs in peripheral blood monocytes, T cells and B cells were measured by flow cytometry at baseline and three-month visits. mRNA expression of JAKs, STATs and suppressors of cytokine signaling (SOCS) were measured from peripheral blood mononuclear cells (PBMCs) by quantitative PCR. Association of baseline signaling profile with treatment response was also investigated.ResultsTofacitinib, in csDMARDs background, decreased median disease activity score (DAS28) from 4.4 to 2.6 (p < 0.001). Tofacitinib treatment significantly decreased cytokine-induced phosphorylation of all JAK-STAT pathways studied. However, the magnitude of the inhibitory effect depended on the cytokine and cell type studied, varying from 10% to 73% inhibition following 3-month treatment with tofacitinib. In general, strongest inhibition by tofacitinib was observed with STAT phosphorylations induced by cytokines signaling through the common-γ-chain cytokine receptor in T cells, while lowest inhibition was demonstrated for IL-10 -induced STAT3 phosphorylation in monocytes. Constitutive STAT1, STAT3, STAT4 and STAT5 phosphorylation in monocytes and/or T cells was also downregulated by tofacitinib. Tofacitinib treatment downregulated the expression of several JAK-STAT pathway components in PBMCs, SOCSs showing the strongest downregulation. Baseline STAT phosphorylation levels in T cells and monocytes and SOCS3 expression in PBMCs correlated with treatment response.ConclusionsTofacitinib suppresses multiple JAK-STAT pathways in cytokine and cell population specific manner in RA patients in vivo. Besides directly inhibiting JAK activation, tofacitinib downregulates the expression of JAK-STAT pathway components. This may modulate the effects of tofacitinib on JAK-STAT pathway activation in vivo and explain some of the differential findings between the current study and previous in vitro studies. Finally, baseline immunological markers associate with the treatment response to tofacitinib.

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Musculoskeletal ultrasound using superb microvascular imaging documents treatment response to biosimilar infliximab in rheumatoid arthritis

BMJ Case Reports ◽

10.1136/bcr-2020-239112 ◽

2021 ◽

Vol 14 (2) ◽

pp. e239112

Author(s):

Julian Alejandro Santos ◽

Cherica Afurong Tee ◽

Romelito Jose Galvan Galsim ◽

Michael Lucas Tee

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Treatment Response ◽

Activity Index ◽

Power Doppler ◽

Musculoskeletal Ultrasound ◽

Joint Effusion ◽

Das 28 ◽

Superb Microvascular Imaging ◽

Microvascular Imaging

A 60-year-old woman with rheumatoid arthritis consulted for acute flare. She had elevated disease activity score 28 - erythrocyte sedimentation rate (DAS 28-ESR) of 6.88 and clinical disease activity index (CDAI) of 32. Her 12-joint ultrasound revealed widespread joint effusion. Synovial vascularity scores measured through superb microvascular imaging (SMI) and power Doppler were universally increased. We documented her treatment response 2 weeks after she received a single dose of biosimilar infliximab using clinical and sonographic data. Her DAS 28-ESR and CDAI scores decreased to 4.21 and 7.0, respectively. Reduction in synovial vascularity scores was demonstrated using SMI. While there was near total resolution in joint effusion and tenosynovitis, SMI was able to demonstrate synovial vascularity in joints with no clinical swelling nor tenderness. Musculoskeletal ultrasound and superb microvascular imaging are useful adjuncts in evaluating synovitis in rheumatoid arthritis and documenting treatment response through documentation of synovial vascularity, effusion and tenosynovitis.

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Calprotectin as a marker of inflammation in patients with early rheumatoid arthritis

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2017-211695 ◽

2017 ◽

Vol 76 (12) ◽

pp. 2031-2037 ◽

Cited By ~ 22

Author(s):

Maria Karolina Jonsson ◽

Nina Paulshus Sundlisæter ◽

Hilde Haugedal Nordal ◽

Hilde Berner Hammer ◽

Anna-Birgitte Aga ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Treatment Response ◽

Radiographic Progression ◽

Activity Index ◽

Inflammatory Marker ◽

Target Therapy ◽

Power Doppler ◽

Treat To Target ◽

Symptom Duration

ObjectivesCalprotectin is an inflammatory marker of interest in rheumatoid arthritis (RA). We evaluated whether the level of calprotectin was associated with disease activity, and if it was predictive of treatment response and radiographic progression in patients with early RA.MethodsPlasma from disease-modifying antirheumatic drug (DMARD)-naïve patients with RA fulfilling 2010 American College of Rheumatology/European League Against Rheumatism classification criteria with symptom duration <2 years was analysed for calprotectin at baseline, and after 1, 3 and 12 months. All patients received treat-to-target therapy, as part of a randomised controlled strategy trial (ARCTIC). The association between calprotectin, erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) and measures of disease activity were assessed by correlations. We used likelihood ratios and logistic regression models to assess the predictive value of the baseline inflammatory markers for treatment response and radiographic damage.Results215 patients were included: 61% female, 82% anti-citrullinated peptide antibody positive, mean (SD) age 50.9 (13.7) years and median (25, 75 percentile) symptom duration 5.8 (2.8, 10.5) months. Calprotectin was significantly correlated with Clinical Disease Activity Index (r=0.32), ESR (r=0.50) and ultrasonography power Doppler (r=0.42) before treatment onset. After 12 months of treatment, calprotectin, but not ESR and CRP, was significantly correlated with power Doppler (r=0.27). Baseline levels of calprotectin, ESR and CRP were not predictive of treatment response, but high levels of calprotectin were associated with radiographic progression in multivariate models.ConclusionsCalprotectin was correlated with inflammation assessed by ultrasound before and during DMARD treatment, and was also associated with radiographic progression. The data support that calprotectin may be of interest as an inflammatory marker when assessing disease activity in different stages of RA.Trial registration numberNCT01205854; Post-results.

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FRI0208 Prediction of treatment response of tocilizumab for rheumatoid arthritis with comprehensive gene expression analysis in peripheral blood mononuclear cells

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2012-eular.2665 ◽

2013 ◽

Vol 71 (Suppl 3) ◽

pp. 384.2-384

Author(s):

Y. Sanayama ◽

K. Ikeda ◽

S. Kagami ◽

S. Furuta ◽

D. Kashiwakuma ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Gene Expression ◽

Treatment Response ◽

Expression Analysis ◽

Peripheral Blood Mononuclear Cells ◽

Peripheral Blood ◽

Gene Expression Analysis ◽

Mononuclear Cells ◽

Peripheral Blood Mononuclear ◽

Blood Mononuclear Cells

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Monitoring of Peripheral Blood Leukocytes and Plasma Samples: A Pilot Study to Examine Treatment Response to Leflunomide in Rheumatoid Arthritis

Pharmaceuticals ◽

10.3390/ph14020106 ◽

2021 ◽

Vol 14 (2) ◽

pp. 106

Author(s):

João F. S. Rodrigues ◽

Liziane C. M. da Silva ◽

Leia Cardoso-Sousa ◽

Douglas Carvalho Caixeta ◽

Debora D. Lückemeyer ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Flow Cytometry ◽

Pilot Study ◽

Side Effects ◽

Treatment Response ◽

Peripheral Blood ◽

Attenuated Total Reflection ◽

Considerable Proportion ◽

World Population ◽

Blood Leukocytes

Rheumatoid arthritis (RA) is a painful inflammatory disease of the joints which affects a considerable proportion of the world population, mostly women. If not adequately treated, RA patients can become permanently disabled. Importantly, not all the patients respond to the available anti-rheumatic therapies, which also present diverse side effects. In this context, monitoring of treatment response is pivotal to avoid unnecessary side effects and costs towards an ineffective therapy. Herein, we performed a pilot study to investigate the potential use of flow cytometry and attenuated total reflection–Fourier transform infrared (ATR-FTIR) spectroscopy as measures to identify responders and non-responders to leflunomide, a disease-modifying drug used in the treatment of RA patients. The evaluation of peripheral blood CD62L+ polymorphonuclear cell numbers and ATR-FTIR vibrational modes in plasma were able to discriminate responders to leflunomide (LFN) three-months after therapy has started. Overall, the results indicate that both flow cytometry and ATR-FTIR can potentially be employed as additional measures to monitor early treatment response to LFN in RA patients.

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