IL11-mediated stromal cell activation may not be the master regulator of pro-fibrotic signaling downstream of TGFβ.

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes.

The Clinical Response of Upadacitinib and Risankizumab Is Associated With Reduced Inflammatory Bowel Disease Anti-TNF-α Inadequate Response Mechanisms.

Background: Janus kinase (JAK) 1 inhibitor upadacitinib and IL-23 inhibitor risankizumab are efficacious in inflammatory bowel disease (IBD) patients who are antitumor necrosis factor (anti-TNF)-α inadequate responders (TNF-IRs). We aimed to understand the mechanisms mediating the response of upadacitinib and risankizumab.

Methods: Eight tissue transcriptomic data sets from IBD patients treated with anti-TNF-α therapies along with single-cell RNAseq data from ulcerative colitis were integrated to identify TNF-IR mechanisms.

Epithelial dysfunction is prevented by IL-22 treatment in a Citrobacter rodentium-induced colitis model that shares similarities with inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal epithelial barrier leading to breach of barrier immunity. Here we identified similar protein expression changes between IBD and Citrobacter rodentium-infected FVB mice with respect to dysregulation of solute transporters as well as components critical for intestinal barrier integrity. We attribute the disease associated changes in the model to the emergence of undifferentiated intermediate intestinal epithelial cells.

Synovial Inflammatory Pathways Characterize Anti-TNF-Responsive Rheumatoid Arthritis Patients.

Objective: This study was undertaken to understand the mechanistic basis of response to anti-tumor necrosis factor (anti-TNF) therapies and to determine whether transcriptomic changes in the synovium are reflected in peripheral protein markers.

Methods: Synovial tissue from 46 rheumatoid arthritis (RA) patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among patients with a good response, a moderate response, or no response, according to the American College of Rheumatology (ACR)/EULAR response criteria.

Lung gene expression and single cell analyses reveal two subsets of idiopathic pulmonary fibrosis (IPF) patients associated with different pathogenic mechanisms.

Idiopathic pulmonary fibrosis is a progressive and debilitating lung disease with large unmet medical need and few treatment options. We describe an analysis connecting single cell gene expression with bulk gene expression-based subsetting of patient cohorts to identify IPF patient subsets with different underlying pathogenesis and cellular changes. We reproduced earlier findings indicating the existence of two major subsets in IPF and showed that these subsets display different alterations in cellular composition of the lung.

Diminished cytokine-induced Jak/STAT signaling is associated with rheumatoid arthritis and disease activity.

Rheumatoid arthritis (RA) is a systemic and incurable autoimmune disease characterized by chronic inflammation in synovial lining of joints. To identify the signaling pathways involved in RA, its disease activity, and treatment response, we adapted a systems immunology approach to simultaneously quantify 42 signaling nodes in 21 immune cell subsets (e.g.

Editing the immune system in vivo in mice using CRISPR/Cas9 ribonucleoprotein (RNP)-mediated gene editing of transplanted hematopoietic stem cells.

CRISPR/Cas9-based genome editing has been widely used to evaluate target gene function in biomedical research. The CRISPR/Cas9 system can introduce gene knockout, knock-in and mutations with more ease than earlier generations of genome editing tools. Using CRISPR/Cas9-based genome editing, researchers have successfully modified the DNA of different immune components, including primary T cells, B cells, macrophages, and immune system progenitors, i.

A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis.

Objective: To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis.

Methods: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26.

Longitudinal Reliability of the OMERACT Thumb Base Osteoarthritis Magnetic Resonance Imaging Scoring System (TOMS).

Objective: To assess the longitudinal reliability of the Outcome Measures in Rheumatology (OMERACT) Thumb base Osteoarthritis Magnetic resonance imaging (MRI) Scoring system (TOMS).

Methods: Paired MRI of patients with hand osteoarthritis were scored in 2 exercises (6-mo and 2-yr followup) for synovitis, subchondral bone defects (SBD), osteophytes, cartilage assessment, bone marrow lesions (BML), and subluxation. Interreader reliability of delta scores was assessed.

Phase IIa, placebo-controlled, randomised study of lutikizumab, an anti-interleukin-1α and anti-interleukin-1β dual variable domain immunoglobulin, in patients with erosive hand osteoarthritis.

Objective: To assess the efficacy, safety, pharmacokinetics and pharmacodynamics of the anti-interleukin (IL)-1α/β dual variable domain immunoglobulin lutikizumab (ABT-981) in erosive hand osteoarthritis (HOA).

Methods: Patients with ≥1 erosive and ≥3 tender and/or swollen hand joints were randomised to placebo or lutikizumab 200 mg subcutaneously every 2 weeks for 24 weeks. The primary endpoint was change in Australian/Canadian Osteoarthritis Hand Index (AUSCAN) pain subdomain score from baseline to 16 weeks.

Molecular taxonomy of osteoarthritis for patient stratification, disease management and drug development: biochemical markers associated with emerging clinical phenotypes and molecular endotypes.

Purpose Of Review: This review focuses on the molecular taxonomy of osteoarthritis from the perspective of molecular biomarkers. We discuss how wet biochemical markers may be used to understand disease pathogenesis and progression and define molecular endotypes of osteoarthritis and how these correspond to clinical phenotypes.

Recent Findings: Emerging evidence suggests that osteoarthritis is a heterogeneous and multifaceted disease with multiple causes, molecular endotypes and corresponding clinical phenotypes.

Soluble biochemical markers of osteoarthritis: Are we close to using them in clinical practice?

Osteoarthritis (OA) is the most common form of arthritis and a major cause of pain and disability. Recent work suggests that the global burden of OA is increasing, and costs associated with treatment are expected to increase dramatically as the aging human population expands. OA is currently diagnosed using radiography, but this technique is an indirect and insensitive measure of alterations in articular cartilage and fails to measure dynamic inflammatory processes in the joint.

Timing and Impact of Decisions to Adjust Disease-Modifying Antirheumatic Drug Therapy for Rheumatoid Arthritis Patients With Active Disease.

Objective: Guidelines recommend that rheumatoid arthritis (RA) patients with moderate-to-high disease activity (MHDAS) adjust disease-modifying antirheumatic drug (DMARD) therapy at least every 3 months until reaching low disease activity or remission (LDAS). We examined how quickly RA patients with MHDAS adjust DMARD therapy in clinical practice, and whether those who adjust DMARDs within 90 days in response to MHDAS reach LDAS sooner.

Methods: We identified RA patients with MHDAS in the University of Pittsburgh Rheumatoid Arthritis Comparative Effectiveness Research registry, and conducted a competing risks regression on time to DMARD therapy adjustment and a Cox regression on time to LDAS.

Rheumatoid Arthritis Patients' Motivations for Accepting or Resisting Disease-Modifying Antirheumatic Drug Treatment Regimens.

Objective: Patient refusal of and nonadherence to treatment with disease-modifying antirheumatic drugs (DMARDs) can adversely affect disease outcomes in rheumatoid arthritis (RA). This qualitative study describes how RA patients' feelings in response to experiences and information affected their decisions to accept (agree to adopt, initiate, and implement) or resist (refuse, avoid, and discontinue) DMARD treatment regimens.

Methods: A total of 48 RA patients were interviewed about their experiences making decisions about DMARDs.

Differential response of serum amyloid A to different therapies in early rheumatoid arthritis and its potential value as a disease activity biomarker.

Background: The aim was to compare the effect of etanercept (ETN) and conventional synthetic disease-modifying anti-rheumatic drug (DMARD) therapy on serum amyloid A (SAA) levels and to determine whether SAA reflects rheumatoid arthritis (RA) disease activity better than C-reactive protein (CRP).

Methods: We measured SAA and CRP at baseline, 24, 48, and 102 week follow-up visits in 594 patients participating in the Treatment of early RA (TEAR) study. We used Spearman correlation coefficients (rho) to evaluate the relationship between SAA and CRP and mixed effects models to determine whether ETN and methotrexate (MTX) treatment compared to triple DMARD therapy differentially lowered SAA.

IgG4-Related Lung Disease Associated with Usual Interstitial Pneumonia.

We report a case of immunoglobulin(Ig)G4-related disease with the radiologic and histopathological manifestations resembling usual interstitial pneumonia (UIP). The patient was a 62-year-old man who presented with progressive dyspnea of insidious onset. High resolution computed tomography of the chest showed lower-lobe predominant peripheral reticulation and traction bronchiectasis but no honeycomb change.

Autoantibody levels in myositis patients correlate with clinical response during B cell depletion with rituximab.

Objectives: To determine the longitudinal trends in serum levels of four myositis-associated autoantibodies: anti-Jo-1, -transcription intermediary factor 1 γ (TIF1-γ), -signal recognition particle (SRP) and -Mi-2, after B cell depletion with rituximab, and to determine the longitudinal association of these autoantibody levels with disease activity as measured by myositis core-set measures (CSMs).

Methods: Treatment-resistant adult and pediatric myositis subjects (n = 200) received rituximab in the 44-week Rituximab in Myositis Trial. CSMs [muscle enzymes, manual muscle testing (MMT), physician and patient global disease activity, HAQ, and extramuscular disease activity] were evaluated monthly and anti-Jo-1 (n = 28), -TIF1-γ (n = 23), -SRP (n = 25) and -Mi-2 (n = 26) serum levels were measured using validated quantitative ELISAs.

Agreement of Physicians and Nurses Performing Tender and Swollen Joint Counts in Rheumatoid Arthritis.

Objective: The aims of this study were to assess the agreement of physicians and nurses performing tender and swollen joint counts (TJCs/SJCs) in rheumatoid arthritis (RA) and identify factors that might influence their examinations including patient age, sex, race, RA disease duration, body mass index, RA disease activity level, comorbid fibromyalgia, comorbid osteoarthritis, and levels of acute-phase reactants.

Methods: Seventy-two RA participants underwent TJCs/SJCs of 28 joints using a standardized protocol by 2 nurses and 2 rheumatologists. Demographic, laboratory, radiographic, and clinical data were obtained to assess the influence of these factors on TJCs/SJCs.

Interferon-regulated chemokine score associated with improvement in disease activity in refractory myositis patients treated with rituximab.

Objectives: The purpose of this study was to investigate whether serum interferon (IFN)-regulated chemokine and distinct cytokine response profiles are associated with clinical improvement in patients with refractory inflammatory myopathy treated with rituximab.

Methods: In a randomised, placebo-phase trial Rituximab in Myositis Trial (RIM), 200 refractory adult and paediatric myositis subjects received rituximab. Following rituximab, clinical response and disease activity were assessed.

Biologic predictors of clinical improvement in rituximab-treated refractory myositis.

Background: To examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoAbs) as predictors of disease improvement in refractory myositis patients treated with rituximab.

Methods: In the RIM Trial, all subjects received rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n = 177) were analyzed at baseline and after rituximab with multiplexed sandwich immunoassays to quantify type-1 IFN-regulated and other pro-inflammatory chemokines and cytokines.

Type I interferon and T helper 17 cells co-exist and co-regulate disease pathogenesis in lupus patients.

Aim: T-helper 17 cells (Th17) and type I interferon (IFN-I) play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies have suggested that IFN-I suppresses Th17 development under autoimmune settings. Therefore, the main objective of this study was to define the association between IFN-I and Th17 pathways in SLE.

Anti-signal recognition particle autoantibody ELISA validation and clinical associations.

Objective: The aim of this study was to develop and validate a quantitative anti-signal recognition particle (SRP) autoantibody serum ELISA in patients with myositis and longitudinal association with myositis disease activity.

Methods: We developed a serum ELISA using recombinant purified full-length human SRP coated on ELISA plates and a secondary antibody that bound human IgG to detect anti-SRP binding. Protein immunoprecipitation was used as the gold standard for the presence of anti-SRP.

Complement component C5a permits the coexistence of pathogenic Th17 cells and type I IFN in lupus.

Systemic lupus erythematosus (SLE) is a type I IFN (IFN-I)-driven autoimmune disorder with exaggerated B and Th cell responses. Th17 cells, a recently identified Th cell subset, have been strongly implicated in the pathogenesis of SLE. Because IFN-I suppresses the generation and expansion of Th17 cells in an IL-27-dependent manner, it is unclear how pathogenic Th17 cells are generated in SLE in the presence of an environment characterized by high IFN-I levels.