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ZongYao Wang,1 John S Sundy,1 Catherine M Foss,1 Huiman X Barnhart,2 Scott M Palmer,1 Sallie D Allgood,3 Evan Trudeau,1 Katie M Alexander,3 Marc C Levesque31Division of Pulmonary, Allergy and Critical Care Medicine, 2Duke Clinical Research Institute, 3Division of Rheumatology and Immunology, Duke University Medical Center, Durham, NC, USABackground: The CD14 C-159T single nucleotide polymorphism (SNP) has been investigated widely as a candidate genetic locus in patients with allergic disease. There are conflicting results for the association of the CD14 C-159T SNP with total serum immunoglobulin E (IgE) levels and atopy. There are limited data regarding the association of the CD14 C-159T SNP in subjects of African ancestry. The aim of the study was to determine whether the C-159T SNP and other CD14 SNPs (C1188G, C1341T) were associated with total serum IgE levels and with allergy skin test results in nonatopic and atopic subjects; as well as in Caucasian and African American subjects.Methods: A total of 291 participants, 18–40 years old, were screened to determine whether they were atopic and/or asthmatic. Analyses were performed to determine the association between CD14 C-159T, C1188G, or C1341T genotypes with serum IgE levels and with the number of positive skin tests among Caucasian or African American subjects.Results: We found no significant association of serum total IgE level with CD14 C-159T, C1188G, or C1341T genotypes within nonatopic or atopic subjects. Subjects with CD14-159 T alleles had significantly more positive allergen skin tests than subjects without CD14-159 T alleles (P = 0.0388). There was a significant association between the CD14 1188 G allele, but not the CD14 1341 T allele, with the number of positive skin-test results in Caucasians, but not in African Americans.Conclusion: These results support a possible association between CD14 polymorphisms and atopy. CD14-159 T or CD14 1188 G alleles were associated with atopic disease. For subjects with CD14 1188 G alleles, the association with atopic disease was stronger in Caucasians compared to African Americans.Keywords: total serum immunoglobulin E, IgE, skin prick test, SPT, CD14-159T, single nucleotide polymorphism, SNP, lipopolysaccharide, LPS, endotoxin

Martine C Lévesque,1,2 Richard Bruce Hovey,2,3 Christophe Bedos2,4 1Faculté de médecine, Université de Montréal, Montréal, QC, Canada; 2Division of Oral Health and Society, Faculty of Dentistry, McGill University, Montreal, QC, Canada; 3Faculty of Medicine, University of Calgary, Calgary, AB, Canada; 4Département de médecine sociale et préventive, Faculté de médicine, Université de Montréal, Montréal, QC, Canada Abstract: Following a historical brief on the development of patient-centered care (PCC), we discuss PCC's value and role in counterbalancing the evidence-based movement in health care. We in turn make a case for a philosophical shift in thinking about the PCC concept, one based on a consideration for how knowledge is produced, used, and valued within care provision processes. A “shared epistemology” foundation is presented, defined, and promoted as essential to the authentic and ethical realization of “shared decision making” between patient and health care provider, and, more generally, of PCC. In accordance with these views, this article critically reviews the literature on health care professional education for the development of PCC. We uncover the disturbing ways in which education frequently undermines the development of patient centeredness, despite curricular emphasis on professionalism and ethical PCC. We also establish the need to raise awareness of how dominant approaches to evaluating student or practitioner performance often fail to reinforce or promote patient centeredness. Finally, we identify successful and inspiring cases of teaching and learning experiences that have achieved perspective transformation on PCC and on new ways of providing care. The pertinence of adopting the theoretical foundations of adult transformative learning is argued, and a call to action is proposed to the leadership of health professional educators across all disciplines. Keywords: patient-centered care, health professional education, transformative learning

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. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFβ signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFβ at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFβ-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis., Competing Interests: Authors YT, KM, QZ, SO’B, MC, SP, SWi, SC, JW, MA, HA-S, DB, AC, KO, BD, BH, JM, CN, DW, CT, AB, FD, VM-T, XL, GS, MW, SA, HK, SWe, LP, TC, LR-B, RSi, KW, LR, BS, YH, LH, AM, WS, IC, SG, GV, CH, TR, RSa, and EF are employees of the company AbbVie. JX, JK, and ML were employees of AbbVie at the time of the study. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Tan, Mosallanejad, Zhang, O’Brien, Clements, Perper, Wilson, Chaulagain, Wang, Abdalla, Al-Saidi, Butt, Clabbers, Ofori, Dillon, Harvey, Memmott, Negron, Winarta, Tan, Biswas, Dong, Morales-Tirado, Lu, Singh, White, Ashley, Knight, Westmoreland, Phillips, Carr, Reinke-Breen, Singh, Xu, Wu, Rinaldi, Stoll, He, Hazelwood, Karman, McCluskey, Stine, Correia, Gauld, Levesque, Veldman, Hubeau, Radstake, Sadhukhan and Fiebiger.)

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. The RNAseq colon tissue data from clinical studies of TNF-IR Crohn's disease patients treated with upadacitinib or risankizumab were used to identify TNF-IR mechanisms that were favorably modified by upadacitinib and risankizumab., Results: We found 7 TNF-IR upregulated modules related to innate/adaptive immune responses, interferon signaling, and tissue remodeling and 6 TNF-IR upregulated cell types related to inflammatory fibroblasts, postcapillary venules, inflammatory monocytes, macrophages, dendritic cells, and cycling B cells. Upadacitinib was associated with a significant decrease in the expression of most TNF-IR upregulated modules in JAK1 responders (JAK1-R); in contrast, there was no change in these modules among TNF-IR patients treated with a placebo or among JAK1 inadequate responders (JAK1-IR). In addition, 4 of the 6 TNF-IR upregulated cell types were significantly decreased after upadacitinib treatment in JAK1-R but not among subjects treated with a placebo or among JAK1-IR patients. We observed similar findings from colon biopsy samples from TNF-IR patients treated with risankizumab., Conclusions: Collectively, these data suggest that upadacitinib and risankizumab affect TNF-IR upregulated mechanisms, which may account for their clinical response among TNF-IR IBD patients., (© The Author(s) 2022. Published by Oxford University Press on behalf of Crohn’s & Colitis Foundation. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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. Serum proteins encoded by synovial genes that were differentially expressed between ACR/EULAR response groups were measured in the same patients., Results: Gene signatures predicted which patients would have good responses, and pathway analysis identified elevated immune pathways, including chemokine signaling, Th1/Th2 cell differentiation, and Toll-like receptor signaling, uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid, and fibroblast cell populations were elevated in good responders relative to nonresponders, consistent with the increased inflammatory pathways. Cell signatures that decreased following anti-TNF treatment were predominately associated with lymphocytes, and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment, and only in good responders, several peripheral inflammatory proteins decreased in a manner that was consistent with corresponding synovial gene changes., Conclusion: Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF treatment may assist in development of predictive markers of patient response and earlier treatment options., (© 2022 American College of Rheumatology.)

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. Prophylactic treatment with IL-22.Fc in C. rodentium-infected FVB mice reduced disease severity and rescued the mice from lethality. Multi-omics and solute analyses revealed that IL-22.Fc treatment prevented disease-associated changes including disruption of the solute transporter machinery and restored proper physiological functions of the intestine, respectively. Taken together, we established the disease relevance of the C. rodentium-induced colitis model to IBD, demonstrated the protective role of IL-22 in amelioration of epithelial dysfunction and elucidated the molecular mechanisms with IL-22's effect on intestinal epithelial cells., (© 2022. The Author(s), under exclusive licence to Society for Mucosal Immunology.)

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.e. hematopoietic stem cells (HSCs), which are also known as Lin-Sca1 + Kit + cells (LSKs) in mice. We previously reported that the transplantation of HSCs with lentivirus-mediated CRISPR/Cas9-based genetic modifications into lethally irradiated congenic mice repopulated the ablated recipient immune system with the donor immune system. In this report, we efficiently manipulated CD40 expression in LSK cells using Cas9 RNP and demonstrated the functional impact in a colitis model. Compared to a virus-based strategy, the RNP approach has the potential to enable investigation of target gene biology in any mouse strain and eliminates the time and effort associated with virus production and infection. Therefore, in vivo RNP-based CRISPR/Cas9 gene editing of transplanted HSCs represents a promising new strategy for exploring gene function in the immune system of mice., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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. We developed classifiers based on the cellular changes in disease to distinguish subsets. Specifically, we showed that one subset of IPF patients had significant increases in gene signature scores for myeloid cells versus a second subset that had significantly increased gene signature scores for ciliated epithelial cells, suggesting a differential pathogenesis among IPF subsets. Ligand-receptor analyses suggested there was a monocyte-macrophage chemoattractant axis (including potentially CCL2-CCR2 and CCL17-CCR4) among the myeloid-enriched IPF subset and a ciliated epithelium-derived chemokine axis (e.g. CCL15) among the ciliated epithelium-enriched IPF subset. We also found that these IPF subsets had differential expression of pirfenidone-responsive genes suggesting that our findings may provide an approach to identify patients with differential responses to pirfenidone and other drugs. We believe this work is an important step towards targeted therapies and biomarkers of response., Competing Interests: All authors are employees of AbbVie, Inc. This does not alter our adherence to PLoS ONE policies on sharing data and materials.

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., IFNα→p-STAT5 in B cells) in peripheral blood mononuclear cells (PBMC) from 194 patients with longstanding RA (including 98 patients before and after treatment), and 41 healthy controls (HC). We found multiple differences between patients with RA compared to HC, predominantly in cytokine-induced Jak/STAT signaling in many immune cell subsets, suggesting pathways that may be associated with susceptibility to RA. We also found that high RA disease activity, compared to low disease activity, was associated with decreased (e.g., IFNα→p-STAT5, IL-10→p-STAT1) or increased (e.g., IL-6→STAT3) response to stimuli in multiple cell subsets. Finally, we compared signaling in patients with established, refractory RA before and six months after initiation of methotrexate (MTX) or TNF inhibitors (TNFi). We noted significant changes from pre-treatment to post-treatment in IFNα→p-STAT5 signaling and IL-10→p-STAT1 signaling in multiple cell subsets; these changes brought the aberrant RA signaling profiles toward those of HC. This large, comprehensive functional signaling pathway study provides novel insights into the pathogenesis of RA and shows the potential of quantification of cytokine-induced signaling as a biomarker of disease activity or treatment response., Competing Interests: The authors have read the journal’s policies and declare the following competing interest: Nodality, Inc., a now inactive company, provided in-kind support for this work and investigators at Nodality played important roles in the study design, hands-on analysis of samples, and preparation of the manuscript. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

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., Results: Little change occurred. Average-measure intraclass correlation coefficients were good-excellent (≥ 0.71), except synovitis (0.55-0.83) and carpometacarpal-1 osteophytes/cartilage assessment (0.47/0.39). Percentage exact/close agreement was 52-92%/68-100%, except BML in 2 years (28%/64-76%). Smallest detectable change was below the scoring increment, except in SBD and BML., Conclusion: TOMS longitudinal reliability was moderate-good. Limited change hampered assessment.

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., Results: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom- and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations., Conclusion: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis., (© 2019, American College of Rheumatology.)

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. At baseline and week 26, subjects had bilateral hand radiographs and MRI of the hand with the greatest number of baseline tender and/or swollen joints. Continuous endpoints were assessed using analysis of covariance models, with treatment and country as main factors and baseline measurements as covariates., Results: Of 132 randomised subjects, 1 received no study drug and 110 completed the study (placebo, 61/67 (91%); lutikizumab, 49/64 (77%)). AUSCAN pain was not different among subjects treated with lutikizumab versus placebo at week 16 (least squares mean difference, 1.5 (95% CI -1.9 to 5.0)). Other clinical and imaging endpoints were not different between lutikizumab and placebo. Lutikizumab significantly decreased serum high-sensitivity C reactive protein levels, IL-1α and IL-1β levels, and blood neutrophils. Lutikizumab pharmacokinetics were consistent with phase I studies and not affected by antidrug antibodies. Injection site reactions and neutropaenia were more common in the lutikizumab group; discontinuations because of adverse events occurred more frequently with lutikizumab (4/64) versus placebo (1/67)., Conclusion: Despite adequate blockade of IL-1, lutikizumab did not improve pain or imaging outcomes in erosive HOA compared with placebo., Competing Interests: Competing interests: AbbVie contributed to the design of the study and was involved in the collection, analysis and interpretation of the data, and in the writing, review and approval of the publication. MK has received grant/research support from Pfizer and been a consultant for AbbVie, GlaxoSmithKline, Merck and Levicept. CP is an employee of Spire Sciences, and is on the speakers' bureau for Amgen and Bristol-Myers Squibb. IKH has been a consultant for AbbVie. FK has no conflicts of interest to declare. RMF has received grant/research support from and has been a consultant for AbbVie. FB has been a consultant for AbbVie, Pfizer and Regeneron. DvdH has been a consultant for AbbVie, Amgen, Astellas, AstraZeneca, Bristol-Myers Squibb, Boehringer-Ingelheim, Celgene, Daiichi, Eli Lilly, Galapagos, Gilead, Janssen, Merck, Novartis, Pfizer, Regeneron, Roche, Sanofi and UCB; she is Director of Imaging Rheumatology. PB is a former employee of PAREXEL, which performed work for this study under contract to AbbVie. RW has been a consultant for AbbVie. SC, LW, WL, GL, YF, MS, JKM and MCL are employees of AbbVie and may own AbbVie stock and/or stock options. SF is a former employee of AbbVie and may own AbbVie stock and/or stock options., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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. Biomarkers may be employed as tools for patient stratification in clinical trials, enhanced disease management in the primary care centres of the future and for directing more rational and targeted osteoarthritis drug development. Proximal molecular biomarkers (e.g synovial fluid) are more likely to distinguish between molecular endotypes because there is less interference from systemic sources of biomarker noise, including comorbidities., Summary: In this review, we have focused on the molecular biomarkers of four distinct osteoarthritis subtypes including inflammatory, subchondral bone remodelling, metabolic syndrome and senescent age-related endotypes, which have corresponding phenotypes. Progress in the field of osteoarthritis endotype and phenotype research requires a better understanding of molecular biomarkers that may be used in conjunction with imaging, pain and functional assessments for the design of more effective, stratified and individualized osteoarthritis treatments.

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., Results: We identified 538 eligible subjects with 943.5 patient-years of followup. Sixty percent of patients with persistent MHDAS adjusted DMARDs within 90 days. Among all subjects, median times to DMARD adjustment and LDAS were 154 (interquartile range [IQR] 1-706) days and 301 (IQR 140-706) days, respectively. Being elderly (subdistribution hazard ratio [SHR] 0.61, P = 0.02), lower baseline disease activity (SHR 0.72, P < 0.01), longer duration of RA (SHR 0.98, P < 0.01), and biologic use (SHR 0.71, P < 0.01) were significantly associated with longer times to therapy adjustment. African American race (hazard ratio [HR] 0.63, P = 0.01), higher baseline disease activity (HR 0.75, P < 0.01), and not adjusting DMARD therapy within 90 days (HR 0.76, P = 0.01) were associated with longer times to LDAS., Conclusion: Adjusting DMARDs within 90 days was associated with shorter times to LDAS, but many patients with persistent MHDAS waited >90 days to adjust DMARDs. Interventions are needed to address the timeliness of DMARD adjustments for RA patients with MHDAS., (© 2017, American College of Rheumatology.)

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. The interviews were transcribed, coded, and analyzed for themes related to their internal motivations for accepting or resisting treatment regimens, using a narrative analysis approach., Results: In addition to feelings about the necessity and dangers of medications, patients' feelings towards their identity as an ill person, the act of taking medication, and the decision process itself were important drivers of patient's decisions. For patients' motivations to accept treatment regimens, 2 themes emerged: a desire to return to a normal life, and fear of future disability due to RA. For motivations to resist treatment regimens, 5 themes emerged: fear of medications, maintaining control over health, denial of sick identity, disappointment with treatment, and feeling overwhelmed by the cognitive burden of deciding., Conclusion: Feelings in response to experiences and information played a major role in how patients weighed the benefits and costs of treatment options, suggesting that addressing patients' feelings may be important when rheumatologists counsel about therapeutic options. Further research is needed to learn how best to address patients' feelings throughout the treatment decision-making process., (© 2017, American College of Rheumatology.)

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. Radiographic changes detected overtime are small and occur in only a subset (progressors) of patients with OA. Therefore, we diagnose patients with OA on the basis of a diagnostic classification that is outdated. We also use the same tools and approaches for assessing the efficacy of new pharmacological and nonpharmacological interventions. In this review, we discuss the utility of soluble biochemical markers as biomarkers of OA and discuss whether we are close to using them in clinical practice. Combining patient information, functional imaging and carefully selected panels of biomarkers can help in achieving enhanced patient stratification and lead to better designed clinical trials. Biomarkers can be used for molecular endotyping and for developing more effective and more personalized treatments that will enhance clinical care for patients with OA., (Copyright © 2018. Published by Elsevier Ltd.)

Purpose: The aim of this "Year in Review" article is to summarize and discuss the implications of biochemical marker related articles published between the Osteoarthritis Research Society International (OARSI) 2015 Congress in Seattle and the OARSI 2016 Congress in Amsterdam., Methods: The PubMed/MEDLINE bibliographic database was searched using the combined keywords: 'biomarker' and 'osteoarthritis'. The PubMed/MEDLINE literature search was conducted using the Advanced Search Builder function (http://www.ncbi.nlm.nih.gov/pubmed/advanced)., Results: Over two hundred new biomarker-related papers were published during the literature search period. Some papers identified new biomarkers whereas others explored the biological properties and clinical utility of existing markers. There were specific references to several adipocytokines including leptin and adiponectin. ADAM Metallopeptidase with Thrombospondin Type 1 motif 4 (ADAMTS-4) and aggrecan ARGS neo-epitope fragment (ARGS) in synovial fluid (SF) and plasma chemokine (CeC motif) ligand 3 (CCL3) were reported as potential new knee biomarkers. New and refined proteomic technologies and novel assays including a fluoro-microbead guiding chip (FMGC) for measuring C-telopeptide of type II collagen (CTX-II) in serum and urine and a novel magnetic nanoparticle-based technology (termed magnetic capture) for collecting and concentrating CTX-II, were described this past year., Conclusion: There has been steady progress in osteoarthritis (OA) biomarker research in 2016. Several novel biomarkers were identified and new technologies have been developed for measuring existing biomarkers. However, there has been no "quantum leap" this past year and identification of novel early OA biomarkers remains challenging. During the past year, OARSI published a set of recommendations for the use of soluble biomarkers in clinical trials, which is a major step forward in the clinical use of OA biomarkers and bodes well for future OA biomarker development., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

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. Akaike information criteria (AIC) were used to determine model fits., Results: SAA levels were only moderately correlated with CRP levels (rho = 0.58, p < 0.0001). There were significant differences in SAA by both visit (p = 0.0197) and treatment arm (p = 0.0130). RA patients treated with ETN plus MTX had a larger reduction in SAA than patients treated with traditional DMARD therapy. Similar results were found for serum CRP by visit (p = 0.0254) and by treatment (p < 0.0001), with a more pronounced difference than for SAA. Across all patients and time points, models of the disease activity score of 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) using SAA levels were better than models using CRP; the ΔAIC between the SAA and CRP models was 305., Conclusions: SAA may be a better biomarker of RA disease activity than CRP, especially during treatment with tumor necrosis factor (TNF) antagonists. This warrants additional studies in other cohorts of patients on treatment for RA., Trial Registration: (ClinicalTrials.gov identifier: NCT00259610 , Date of registration: 28 November 2005).

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. Microscopic examination of the surgical lung biopsy showed characteristic features of UIP including architectural distortion by fibrosis with peripheral and paraseptal accentuation, scattered fibroblast foci and microscopic honeycomb change. In addition there were prominent multifocal lymphoplasmacytic infiltrates with a marked increase of IgG4-positive plasma cells (79 per high power field in hot spots) and high IgG4/IgG ratio (up to 67%). The serum IgG4 level was elevated at 760 mg/dl (reference range 9-89), with normal levels for the other IgG subclasses and negative serologic markers for autoimmune diseases. The patient's symptoms improved significantly with oral corticosteroid treatment.

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. Intraclass correlations (ICCs) among examiners were determined for TJCs/SJCs. Nurse-physician differences and agreement of individual joints were evaluated using Cohen κ. Analysis of variance was performed to detect differences in means between examiners for TJCs/SJCs. Intraclass correlation and Fisher Z tests were used to identify factors influencing TJCs/SJCs., Results: Agreement was strong among these nurses and physicians for total TJCs/SJCs (ICC = 0.84/ICC = 0.79, respectively). κ was best for hand joint tenderness and poorest for shoulder swelling. Some significant differences in mean TJCs/SJCs were found between examiners. Fibromyalgia significantly reduced agreement of both TJCs and SJCs. Agreement of TJC was significantly reduced when patients had lower disease activity, greater work impairment, lower mental health quality of life, and elevated erythrocyte sedimentation rate, whereas female sex, assessor's perception of but not radiographic hand osteoarthritis, and elevated C-reactive protein significantly reduced agreement for SJC., Conclusions: Strong agreement was found among nurses and physicians for total 28-joint counts, with agreement at individual joints being stronger for tenderness than swelling. Fibromyalgia significantly reduced ICCs of TJCs/SJCs.

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. Biomarker scores were generated for the following pathways: type-1 IFN-inducible (IFNCK), innate, Th1, Th2, Th17 and regulatory cytokines. Myositis autoAbs (anti-synthetase n = 28, TIF-γ n = 19, Mi-2 n = 25, SRP n = 21, MJ n = 18, non-MAA n = 24, unidentified autoantibody n = 9, and no autoantibodies n = 33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum tests were used for comparisons., Results: The mean (SD) values for muscle disease and physician global disease activity VAS scores (0-100 mm) were 46 (22) and 49 (19). IFNCK scores (median values) were higher at baseline in subjects with anti-synthetase (43), TIF1-γ (31) and Mi-2 (30) compared with other autoAb groups (p < 0.001). At 16 weeks after rituximab, anti-synthetase and Mi-2 autoAb positive subjects and non-MAA had a greater improvement in IFNCK scores (- 6.7, - 6.1 and -7.2, p < .001). Both IFNCK high scores (>30) and autoAb group (Mi-2, non-MAA, and undefined autoantibody) demonstrated the greatest clinical improvement based on muscle VAS (muscle-interaction p = 0.075)., Conclusion: Biomarker signatures in conjunction with autoAbs help predict response to rituximab in refractory myositis. Biomarker and clinical responses are greatest at 16 weeks after 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. Serum samples and clinical data were collected at baseline and several time-points after rituximab treatment. Multiplexed sandwich immunoassays quantified serum levels of IFN-regulated chemokines and other pro-inflammatory cytokines. Composite IFN-regulated chemokine and Th1, Th2, Th17 and regulatory cytokine scores were computed., Results: Baseline IFN-regulated chemokine, Th1, Th2, Th17 and regulatory cytokine scores correlated with baseline physician global VAS, whereas the baseline Th1, Th2 and Th17 cytokine scores correlated with baseline muscle VAS. We also found baseline IFN-regulated chemokine scores correlated with specific non-muscular targets such as baseline cutaneous (r=0.29; p=0.002) and pulmonary (r=0.18; p=0.02) VAS scores. Among all cytokine/chemokines examined, the baseline score of IFN-regulated chemokines demonstrated the best correlation with changes in muscle VAS at 8 (r=-0.19; p=0.01) and 16 weeks (r=-0.17; p=0.03) following rituximab and physician global VAS at 16 weeks (r=-0.16; p=0.04). In vitro experiments showed increased levels of IL-8 (p=0.04), MCP-1 (p=0.04), IL-6 (p=0.03), IL-1β (p=0.04), IL-13 (p=0.04), IL-10 (p=0.02), IL-2 (p=0.04) and IFN-γ (p=0.02) in supernatants of TLR-3 stimulated PBMCs from non-responder compared to patients responders to rituximab., Conclusions: IFN-regulated chemokines before treatment is associated with improvement in disease activity measures in refractory myositis patients treated with rituximab.

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., Methods: Peripheral blood samples and disease activity measures were collected from 31 patients fulfilling the American College of Rheumatology revised criteria for SLE. Serum was evaluated for IFN-α bioactivity and interleukin (IL)-6 levels by cell-based bioluminescence assay and enzyme-linked immunosorbent assay, respectively. The frequency of Th17 cells in peripheral blood was determined by intracellular cytokine staining for IL-17., Results: IFN-α bioactivity in the serum of lupus subjects (mean ± SD: 6.510 ± 3.686) was significantly higher (P = 0.001) compared to healthy controls (2.9 ± 1.061). Additionally, 58.1% and 41.9% of SLE subjects displayed high and low IFN-α bioactivity, respectively. We observed a significant increase (P = 0.04) in the percentage of Th17 cells in lupus subjects with high IFN-α bioactivity (1.9 ± 1.0) compared to lupus subjects with low IFN-α bioactivity (1.2 ± 0.9). Lupus subjects with high IFN-α bioactivity and Th17 cells had significantly higher disease activity (P = 0.04) and serum IL-6 levels (P = 0.01) compared to patients with low IFN-α activity and low Th17 cells., Conclusion: Type I interferon and Th17 pathways co-exist and co-regulate the pathogenic processes in SLE. Additionally, these studies clearly identify IL-6 as a common link between IFN-I and Th17 pathways in SLE pathogenesis., (© 2015 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

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. Serum samples from three groups were analysed: SRP(+) myositis subjects by immunoprecipitation, SRP(-) myositis subjects by immunoprecipitation and non-myositis controls. The ELISA's sensitivity, specificity, positive predictive value and negative predictive value were evaluated. Percentage agreement and test-retest reliability were assessed. Serial samples from seven SRP immunoprecipitation-positive subjects were also tested, along with serum muscle enzymes and manual muscle testing., Results: Using immunoprecipitation, we identified 26 SRP(+) myositis patients and 77 SRP(-) controls (including 38 patients with necrotizing myopathy). Non-myositis control patients included SLE (n = 4) and SSc (n = 7) patients. Anti-SRP positivity by ELISA showed strong agreement (97.1%) with immunoprecipitation (κ = 0.94). The sensitivity, specificity, positive predictive value, and negative predictive value of the anti-SRP ELISA were 88, 100, 100 and 96, respectively. The area under the curve was 0.94, and test-retest reliability was strong (r = 0.91, P < 0.001). Serial samples showed that anti-SRP levels paralleled changes in muscle enzymes and manual muscle testing., Conclusion: We developed a quantitative ELISA for detecting serum anti-SRP autoantibodies and validated the assay in myositis. Longitudinal assessment of SRP levels by ELISA may be a useful biomarker for disease activity., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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. In this study, we showed that activation of c5aR on murine macrophages blocked IFN-I-mediated IL-27 production, thus permitting the development of Th17 cells. C5aR activation on IFN-I-responsive macrophages inhibits IRF-1-mediated transactivation of IL-27 gene expression via the PI3K/Akt pathway. Consistently, C5aR-deficient mice exhibited increased IL-27 expression and fewer Th17 cells and consequently developed reduced lupus nephritis in comparison with wild-type mice. In support of these findings in mice, we found that C5a inhibited IFN-I-induced IL-27 production from macrophages of lupus subjects. Moreover, the level of serum C5a correlated with Th17 frequency in peripheral blood. Collectively, these data indicate an essential role for C5a in the generation of pathogenic Th17 responses in SLE. Thus, therapeutic strategies to block C5aR activation may be beneficial for controlling pathogenic Th17-mediated inflammation in SLE., (Copyright © 2012 by The American Association of Immunologists, Inc.)

Objective: To identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab., Methods: We analyzed data for 195 patients with myositis (75 with adult polymyositis [PM], 72 with adult dermatomyositis [DM], and 48 with juvenile DM) in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of the following 6 core set measures of disease activity: physician's and patient's/parent's global assessment of disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, core set measures, rituximab treatment, and myositis autoantibodies (antisynthetase, anti-Mi-2, anti-signal recognition particle, anti-transcription intermediary factor 1γ [TIF-1γ], anti-MJ, other autoantibodies, and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement., Results: In the final multivariable model, the presence of an antisynthetase, primarily anti-Jo-1 (hazard ratio [HR] 3.08, P < 0.01), anti-Mi-2 (HR 2.5, P < 0.01), or other autoantibody (HR 1.4, P = 0.14) predicted a shorter time to improvement compared to the absence of autoantibodies. A lower physician's global assessment of damage (HR 2.32, P = 0.02) and juvenile DM (versus adult myositis) (HR 2.45, P = 0.01) also predicted improvement. Unlike autoantibody status, the predictive effect of physician's global assessment of damage and juvenile DM diminished by week 20. Rituximab treatment did not affect these associations., Conclusion: Our findings indicate that the presence of antisynthetase and anti-Mi-2 autoantibodies, juvenile DM subset, and lower disease damage strongly predict clinical improvement in patients with refractory myositis., (Copyright © 2014 by the American College of Rheumatology.)

Objectives: A quantitative anti-transcription intermediary factor 1-gamma (anti-TIF1-γ) ELISA may improve the detection of cancer-associated myositis (CAM). The aims of this study were the development and validation of a quantitative anti-TIF1-γ autoantibody ELISA in patients with myositis., Methods: We developed an ELISA using recombinant purified full-length human TIF1-γ. Patient serum was incubated with TIF1-γ-coated ELISA plates, and secondary antibody that bound human IgG was used to detect anti-TIF1-γ binding. Protein immunoprecipitation (IP) was used as the gold standard for the presence of anti-TIF1-γ. Serum samples from myositis patients with positive and negative anti-TIF1-γ by IP, from non-myositis autoimmune patients (SSc, SLE and RA) and from healthy controls were analysed. The ELISA's sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were evaluated. Agreement between the ELISA and IP results was determined using chi-squared and kappa tests. Test-retest reliability of the ELISA was assessed., Results: We identified 55 myositis patients with and 111 controls without anti-TIF1-γ by IP. Anti-TIF1-γ positivity by ELISA showed strong agreement (93.9%) with IP results (κ = 0.87). The sensitivity, specificity, PPV, NPV and overall accuracy of the anti-TIF1-γ ELISA were 91%, 96%, 93%, 95% and 94%, respectively. The area under the curve (AUC) of a receiver operating characteristic (ROC) curve was 0.938. Test-retest reliability was strong (Pearson r = 0.913, P < 0.001)., Conclusion: We developed a quantitative ELISA for detecting serum anti-TIF1-γ autoantibodies and validated the assay in myositis and other connective tissue disease patients. The availability of a validated, quantitative ELISA should improve the detection of anti-TIF1-γ autoantibodies and may improve the detection of CAM.

Introduction: Subjects with primary Sjögren's syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab., Methods: To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period., Results: Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection., Conclusions: For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B-cell populations in humans.

Introduction: Accumulating data implicate the CD4+ T cell subset (Th17 cells) in rheumatoid arthritis (RA). IL-17 is an inflammatory cytokine that induces tumor necrosis factor (TNF)α, IL-1β and IL-6, all of which are targets of biologic therapies used to treat RA. RA patients are well documented to experience more infections than age-matched controls, and biologic therapies further increase the risk of infection. The Th17/IL-17 axis is vital for immunity to fungi, especially the commensal fungus Candida albicans. Therefore, we were prompted to examine the relationship between RA and susceptibility to C. albicans because of the increasing interest in Th17 cells and IL-17 in driving autoimmunity, and the advent of new biologics that target this pathway., Methods: We analyzed peripheral blood and saliva from 48 RA and 33 healthy control subjects. To assess C. albicans-specific Th17 responses, PBMCs were co-cultured with heat-killed C. albicans extract, and IL-17A levels in conditioned supernatants were measured by ELISA. The frequency of Th17 and Th1 cells was determined by flow cytometry. As a measure of IL-17A-mediated effector responses, we evaluated C. albicans colonization rates in the oral cavity, salivary fungicidal activity and levels of the antimicrobial peptide β-defensin 2 (BD2) in saliva., Results: Compared to controls, PBMCs from RA subjects exhibited elevated baseline production of IL-17A (P = 0.004), although they had similar capacity to produce IL-17A in response to Th17 cell differentiating cytokines (P = 0.91). However RA PBMCs secreted less IL-17A in response to C. albicans antigens (P = 0.006). Significantly more RA patients were colonized with C. albicans in the oral cavity than healthy subjects (P = 0.02). Concomitantly, RA saliva had reduced concentrations of salivary BD2 (P = 0.02). Nonetheless, salivary fungicidal activity was preserved in RA subjects (P = 0.70)., Conclusions: RA subjects exhibit detectable impairments in oral immune responses to C. albicans, a strongly Th17-dependent opportunistic pathogen, despite an overall elevated baseline production of IL-17A.

We hypothesized B cells are involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a progressive, restrictive lung disease that is refractory to glucocorticoids and other nonspecific therapies, and almost invariably lethal. Accordingly, we sought to identify clinically associated B cell-related abnormalities in these patients. Phenotypes of circulating B cells were characterized by flow cytometry. Intrapulmonary processes were evaluated by immunohistochemistry. Plasma B lymphocyte stimulating factor (BLyS) was assayed by ELISA. Circulating B cells of IPF subjects were more Ag differentiated, with greater plasmablast proportions (3.1 ± 0.8%) than in normal controls (1.3 ± 0.3%) (p < 0.03), and the extent of this differentiation correlated with IPF patient lung volumes (r = 0.44, p < 0.03). CD20(+) B cell aggregates, diffuse parenchymal and perivascular immune complexes, and complement depositions were all prevalent in IPF lungs, but much less prominent or absent in normal lungs. Plasma concentrations of BLyS, an obligate factor for B cell survival and differentiation, were significantly greater (p < 0.0001) in 110 IPF (2.05 ± 0.05 ng/ml) than among 53 normal (1.40 ± 0.04 ng/ml) and 90 chronic obstructive pulmonary disease subjects (1.59 ± 0.05 ng/ml). BLyS levels were uniquely correlated among IPF patients with pulmonary artery pressures (r = 0.58, p < 0.0001). The 25% of IPF subjects with the greatest BLyS values also had diminished 1-y survival (46 ± 11%), compared with those with lesser BLyS concentrations (81 ± 5%) (hazard ratio = 4.0, 95% confidence interval = 1.8-8.7, p = 0.0002). Abnormalities of B cells and BLyS are common in IPF patients, and highly associated with disease manifestations and patient outcomes. These findings have implications regarding IPF pathogenesis and illuminate the potential for novel treatment regimens that specifically target B cells in patients with this lung disease.

Rheumatoid arthritis (RA) is a complex inflammatory disorder associated with synovitis and joint destruction that affects an estimated 1·3 million Americans and causes significant morbidity, a reduced life-span and lost work productivity. The use of biological therapies for the treatment of RA is costly, and the selection of therapies is still largely empirical and not guided by the underlying biological features of the disease in individual patients. The synovitis associated with RA is characterized by an influx of B and T cells, macrophages and neutrophils and the expansion of fibroblast-like synoviocytes, which form pannus and lead to cartilage and bone destruction. RA is associated with synovial production of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) and with the production of inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-17 and tumour necrosis factor (TNF)-α, which are targets for RA therapeutics. Recent ideas about the pathogenesis of RA emphasize a genetic predisposition to develop RA, a preclinical phase of disease that is associated with the production of ACPA and the development of symptomatic disease following inflammatory initiating events that are associated with expression of citrullinated epitopes in the joints of patients. However, we still have a limited understanding of the cytokine and intracellular pathways that regulate ACPA levels. In humans, therapy with biological agents affords a unique opportunity to better understand the cytokine and signalling pathways regulating ACPA levels and the impact of ACPA level changes on disease activity. In this study we summarize the effect of RA therapies on ACPA levels and B cell responses., (© 2013 British Society for Immunology.)

Objective: To study the safety and clinical efficacy of rituximab therapy for primary Sjögren's syndrome, as well as to investigate its mechanisms., Methods: Patients with primary Sjögren's syndrome were enrolled in an open-label trial, were given rituximab (1 gm) infusions on days 1 and 15, and were monitored through week 52. The primary end point was safety, with secondary end points evaluating clinical and biologic efficacy. Blood was obtained for enumeration of lymphocyte subsets, measurement of serum autoantibody and BAFF levels, and analysis of gene expression., Results: Twelve female patients with primary Sjögren's syndrome were administered rituximab. They had a median age of 51 years (range 34-69 years) and a median disease duration of 8.0 years (range 2-18 years). We observed no unexpected toxicities from the rituximab therapy. Modest improvements were observed at week 26 in patient-reported symptoms of fatigue and oral dryness, with no significant improvement in the objective measures of lacrimal and salivary gland function. The recovery of blood B cells following the nadir from rituximab therapy was characterized by a predominance of transitional B cells and a lack of memory B cells. While blood B cell depletion was associated with an increase in serum BAFF levels, no significant changes were observed in the levels of serum anti-Ro/SSA, anti-La/SSB, and anti-type 3 muscarinic acetylcholine receptor autoantibodies or in the blood interferon signature., Conclusion: In patients with primary Sjögren's syndrome, a single treatment course of rituximab was not associated with any unexpected toxicities and led to only modest clinical benefits despite effective depletion of blood B cells., (Copyright © 2013 by the American College of Rheumatology.)

Rationale: Diverse autoantibodies are present in most patients with idiopathic pulmonary fibrosis (IPF). We hypothesized that specific autoantibodies may associate with IPF manifestations., Objectives: To identify clinically relevant, antigen-specific immune responses in patients with IPF., Methods: Autoantibodies were detected by immunoblots and ELISA. Intrapulmonary immune processes were evaluated by immunohistochemistry. Anti-heat shock protein 70 (HSP70) IgG was isolated from plasma by immunoaffinity. Flow cytometry was used for leukocyte functional studies., Measurements and Main Results: HSP70 was identified as a potential IPF autoantigen in discovery assays. Anti-HSP70 IgG autoantibodies were detected by immunoblots in 3% of 60 control subjects versus 25% of a cross-sectional IPF cohort (n = 122) (P = 0.0004), one-half the patients with IPF who died (P = 0.008), and 70% of those with acute exacerbations (P = 0.0005). Anti-HSP70 autoantibodies in patients with IPF were significantly associated with HLA allele biases, greater subsequent FVC reductions (P = 0.0004), and lesser 1-year survival (40 ± 10% vs. 80 ± 5%; hazard ratio = 4.2; 95% confidence interval, 2.0-8.6; P < 0.0001). HSP70 protein, antigen-antibody complexes, and complement were prevalent in IPF lungs. HSP70 protein was an autoantigen for IPF CD4 T cells, inducing lymphocyte proliferation (P = 0.004) and IL-4 production (P = 0.01). IPF anti-HSP70 autoantibodies activated monocytes (P = 0.009) and increased monocyte IL-8 production (P = 0.049). ELISA confirmed the association between anti-HSP70 autoreactivity and IPF outcome. Anti-HSP70 autoantibodies were also found in patients with other interstitial lung diseases but were not associated with their clinical progression., Conclusions: Patients with IPF with anti-HSP70 autoantibodies have more near-term lung function deterioration and mortality. These findings suggest antigen-specific immunoassays could provide useful clinical information in individual patients with IPF and may have implications for understanding IPF progression.

Objective: To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase trial in adult and pediatric myositis patients., Methods: Adults with refractory polymyositis (PM) and adults and children with refractory dermatomyositis (DM) were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal values on core set measures (CSMs) for adults. Juvenile DM patients required ≥3 abnormal CSMs, with or without muscle weakness. Patients were randomized to receive either rituximab early or rituximab late, and glucocorticoid or immunosuppressive therapy was allowed at study entry. The primary end point compared the time to achieve the International Myositis Assessment and Clinical Studies Group preliminary definition of improvement (DOI) between the 2 groups. The secondary end points were the time to achieve ≥20% improvement in muscle strength and the proportions of patients in the early and late rituximab groups achieving the DOI at week 8., Results: Among 200 randomized patients (76 with PM, 76 with DM, and 48 with juvenile DM), 195 showed no difference in the time to achieving the DOI between the rituximab late (n = 102) and rituximab early (n = 93) groups (P = 0.74 by log rank test), with a median time to achieving a DOI of 20.2 weeks and 20.0 weeks, respectively. The secondary end points also did not significantly differ between the 2 treatment groups. However, 161 (83%) of the randomized patients met the DOI, and individual CSMs improved in both groups throughout the 44-week trial., Conclusion: Although there were no significant differences in the 2 treatment arms for the primary and secondary end points, 83% of adult and juvenile myositis patients with refractory disease met the DOI. The role of B cell-depleting therapies in myositis warrants further study, with consideration for a different trial design., (Copyright © 2013 by the American College of Rheumatology.)

Objective: Up to 90% of adults with rheumatoid arthritis (RA) in clinical remission have persistent synovitis and/or bone marrow lesions (BMLs) on magnetic resonance imaging (MRI). MRI findings in patients with juvenile idiopathic arthritis (JIA) in clinical remission have not been described. We utilized 3T MRI with contrast enhancement to examine JIA patients with hand and/or wrist involvement who were in clinical remission and compared them with a cohort of adult RA patients., Methods: In total, 11 JIA patients and 10 RA patients with arthritis involving the hands and/or wrists were identified by their primary rheumatologist as being in physician-defined clinical remission, having no signs or symptoms of active arthritis and no medication changes for at least 6 months. A study rheumatologist performed a joint evaluation for tenderness, swelling, and limitation of motion, and study participants self-reported tender joint counts. The participants underwent MRI with intravenous contrast enhancement of 1 hand and wrist with a history of prior symptoms. A pediatric musculoskeletal radiologist blinded to the clinical data scored the MRIs for synovitis, tenosynovitis, and/or BMLs., Results: Sixty-three percent of the JIA cohort and 70% of the RA cohort had MRI findings of synovitis, BMLs, and/or tenosynovitis. All pediatric patients with MRI abnormalities had normal physician tender and swollen joint counts. The patients' self-report of painful joint counts did not predict MRI abnormalities., Conclusion: Over one-half of the patients in clinical remission had MRI evidence of persistent inflammation, defined as the presence of synovitis, tenosynovitis, or BMLs. A substantial portion of patients with JIA may have subclinical disease despite clinical remission., (Copyright © 2012 by the American College of Rheumatology.)

Rheumatoid arthritis (RA) affects an estimated 1.3 million Americans and is a complex inflammatory disease associated with synovitis and joint destruction. The development of biologic disease-modifying anti-rheumatic drugs (DMARDs) that target specific mediators of inflammation has led to several highly successful therapies for the treatment of RA. The imperfect efficacy of biologic DMARDs has resulted in the absence of clear guidelines on how biologic DMARDs should be used in the clinic to optimize treatment of RA patients. This makes it imperative that better data be available to physicians and RA patients about the comparative effectiveness of different biologic DMARDs. Prior to 2008, there were no randomized trials comparing biologic DMARDs for the treatment of RA. Since then, there have been published studies that directly compared biologic DMARDs for the treatment of RA, and several studies that estimated the relative efficacy of different biologic DMARDs by comparing published results of studies that included treatment of RA patients with biologic DMARDs who had previously experienced an inadequate response to methotrexate or tumor necrosis factor (TNF) antagonists. There are two recent studies that directly compared biologic DMARDs with optimal combinations of oral DMARDs and these are important because there are significant differences in costs and side effects between oral and biologic DMARDs. Among the studies that directly compared biologic DMARDs, it has been reported that RA patients who fail a TNF antagonist have a higher response rate (based on disease activity score [DAS28] measurements) to treatment with rituximab as compared with another TNF antagonist. In addition, in the ATTEST trial, the investigators found that, for RA patients with an inadequate response to methotrexate, treatment with abatacept versus infliximab resulted in response rates that were roughly equal. There are also several head-to-head studies of biologic DMARDs that are currently enrolling or about to enroll RA subjects. Pharmaceutical companies have taken more interest in comparative effectiveness studies, in part due to the emphasis that has been placed on this type of research by the US federal government and associated organizations including the Patient-Centered Outcomes Research Institute (PCORI). Therefore, while there is currently a relative lack of comparative effectiveness research to inform clinical decisions about biologic DMARDs for RA patients, it appears likely that there will be wider availability of such data in the near future.