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Objective: We analyzed the impact of amino acid (AA) availability on the inflammatory response in arthritis., Methods: We stimulated rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLSs) with tumor necrosis factor (TNF) in the presence or absence of proteinogenic AAs and measured their response by QuantSeq 3' messenger RNA sequencing, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. Signal transduction events were determined by Western blot. We performed K/BxN serum transfer arthritis in mice receiving a normal and a low-protein diet and analyzed arthritis clinically and histologically., Results: Deprivation of AAs decreased the expression of a specific subset of genes, including the chemokines CXCL10, CCL2, and CCL5 in TNF-stimulated FLSs. Mechanistically, the presence of AAs was required for the TNF-induced activation of an interferon regulatory factor 1 (IRF1)-STAT1 signaling circuit that drives the expression of chemotactic factors. The expression of IRF1 and the IRF1-dependent gene set in FLSs was highly correlated with the presence of inflammatory cells in human RA, emphasizing the important role of this AA-dependent pathway in inflammatory cell recruitment to the synovial tissue. Finally, we show that mice receiving a low-protein diet expressed less IRF1 in the inflamed synovium and consequently developed reduced clinical and histologic signs of arthritis., Conclusion: AA deprivation reduces the severity of arthritis by suppressing the expression of IRF1-STAT1-driven chemokines, which are crucial for leukocyte recruitment to the arthritic joint. Overall, our study provides novel insights into critical determinants of inflammatory arthritis and may pave the way for dietary intervention trials in RA., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response., Methods: We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response., Results: Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC., Conclusions: Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy., Competing Interests: Competing interests: PM reports speaker fees from AbbVie, Janssen and Novartis and research grants from AbbVie, BMS, Novartis, Janssen, MSD and UCB. HH received grants from Glock Health, BlueSky Immunotherapies and Neutrolis. JS is the President of the Austrian Society of Rheumatology and Rehabilitation (unpaid position). HB received consulting fees from MSD, Pfizer, Takeda and Gilead, speaker fees from Shionogi, Pfizer and MSD, advisory boards for Valneva, MSD and Gilead. DA reports grants from AbbVie, Amgen, Lilly, Novartis, Roche, SoBi and Sanofi, other from AbbVie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche and Sandoz, outside the submitted work. SB reports personal fees from AbbVie and personal fees from Novartis, outside the submitted work. ES reports support for meeting attendances from Pfizer and Bristol Myers Squibb., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

For the identification of antigenic protein biomarkers for rheumatoid arthritis (RA), we conducted IgG profiling on high density protein microarrays. Plasma IgG of 96 human samples (healthy controls, osteoarthritis, seropositive and seronegative RA, n = 24 each) and time-series plasma of a pristane-induced arthritis (PIA) rat model ( n = 24 total) were probed on AIT's 16k protein microarray. To investigate the analogy of underlying disease pathways, differential reactivity analysis was conducted. A total of n = 602 differentially reactive antigens (DIRAGs) at a significance cutoff of p < 0.05 were identified between seropositive and seronegative RA for the human samples. Correlation with the clinical disease activity index revealed an inverse correlation of antibodies against self-proteins found in pathways relevant for antigen presentation and immune regulation. The PIA model showed n = 1291 significant DIRAGs within acute disease. Significant DIRAGs for (I) seropositive, (II) seronegative and (III) PIA were subjected to the Reactome pathway browser which also revealed pathways relevant for antigen presentation and immune regulation; of these, seven overlapping pathways had high significance. We therefore conclude that the PIA model reflects the biological similarities of the disease pathogenesis. Our data show that protein array analysis can elucidate biological differences and pathways relevant in disease as well be a useful additional layer of omics information.

Objectives: Identification of trajectories of radiographic damage in rheumatoid arthritis (RA) by clustering patients according to the shape of their curve of Sharp-van der Heijde scores (SHSs) over time. Developing models to predict their progression cluster from baseline characteristics., Methods: Patient-level data over a 2-year period from five large randomised controlled trials on tumour necrosis factor inhibitors in RA were used. SHSs were clustered in a shape-respecting manner to identify distinct clusters of radiographic progression. Characteristics of patients within different progression clusters were compared at baseline and over time. Logistic regression models were developed to predict trajectory of radiographic progression using information at baseline., Results: In total, 1887 patients with 7738 X-rays were used for cluster analyses. We identified four distinct clusters with characteristic shapes of radiographic progression: one with a stable SHS over the whole 2-year period (C0/lowChange; 86%); one with relentless progression (C1/rise; 5.8%); one with decreasing SHS (C2/improvement; 6.9%); one going up and down (C3/bothWays; 1.4%) of the SHS. Robustness of clusters were confirmed using different clustering methods. Regression models identified disease duration, baseline C-reactive protein (CRP) and SHS and treatment status as predictors for cluster assignment., Conclusions: We were able to identify and partly characterise four different clusters of radiographic progression over time in patients with RA, most remarkably one with relentless progression and another one with amelioration of joint damage over time, suggesting the existence of distinct patterns of joint damage accrual in RA., Competing Interests: Competing interests: HR, AP, FA: nothing to declare. DA reports grants from Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi, other from Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, outside the submitted work; JSS received grants to his institution from Abbvie, AstraZeneca, Janssen, Lilly, Merck Sharpe & Dohme, Pfizer and Roche, and provided expert advice for, or had symposia speaking engagements with, AbbVie, Amgen, AstraZeneca, Astro, Bristol-Myers Squibb, Celgene, Celltrion, Chugai, Gilead, ILTOO Pharma, Janssen, Lilly, Merck Sharp & Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi and UCB. SB reports personal fees from Abbvie, personal fees from Novartis, outside the submitted work., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: NKG2D ligands (NKG2DLs) are stress-inducible molecules involved in multiple inflammatory settings. In this work, we quantified MICA, an NKG2DL, in the synovial fluid of patients suffering various arthritides and measured Nkg2dLs gene expression in murine models of acute joint inflammation., Methods: Soluble MICA (sMICA) was quantified by ELISA is synovial fluids harvested from patients suffering osteoarthritis, rheumatoid arthritis, psoriatic arthritis, calcium pyrophosphate crystal arthritis, urate crystal arthritis and reactive arthritis. Transcripts encoding murine NKG2DLs were quantified by RT-qPCR in the joints of mouse models of rheumatoid arthritis, urate crystal arthritis and osteoarthritis., Results: Marked overproduction of sMICA was observed in the synovial fluid of RA patients. Mouse studies highlighted the complex transcriptional regulation of Nkg2d ligands encoding genes depending on the inflammatory setting and microenvironment CONCLUSIONS: sMICA quantification could be an interesting biomarker to identify acute inflammation in RA patients in whom classical markers (i.e. anti-citrullinated protein antibodies, ACPA) are undetectable.

Animal models for inflammatory arthritides such as rheumatoid arthritis (RA) and psoriatic arthritis are widely accepted and frequently used to identify pathological mechanisms and validate novel therapeutic strategies. Unfortunately, many publications reporting on these animal studies lack detailed description and appropriate assessment of the distinct histopathological features of arthritis: joint inflammation, cartilage damage and bone erosion. Therefore, the European consortium BeTheCure, consisting of 38 academic and industrial partners from 15 countries, set as goal to standardise the histological evaluation of joint sections from animal models of inflammatory arthritis. The consensual approach of a task force including 16 academic and industrial scientists as well as laboratory technicians has resulted in the development of the Standardised Microscopic Arthritis Scoring of Histological sections ('SMASH') recommendations for a standardised processing and microscopic scoring of the characteristic histopathological features of arthritis, exemplified by four different rodent models for arthritis: murine collagen-induced arthritis, collagen-antibody-induced arthritis, human tumour necrosis factor transgenic Tg197 mice and rat pristane-induced arthritis, applicable to any other inflammatory arthritis model. Through standardisation, the SMASH recommendations are designed to improve and maximise the information derived from in vivo arthritis experiments and to promote reproducibility and transparent reporting on such studies. In this manuscript, we will discuss and provide recommendations for analysis of histological joint sections: identification of the regions of interest, sample preparation, staining procedures and quantitative scoring methods. In conclusion, awareness of the different features of the arthritis pathology in animal models of inflammatory arthritis is of utmost importance for reliable research outcome, and the standardised histological processing and scoring methods in these SMASH recommendations will help increase uniformity and reproducibility in preclinical research on inflammatory arthritis., Competing Interests: Competing interests: MCD, CG and GK report personal fees from Biomedcode, outside the submitted work; and Biomedcode is a service provider of in vivo efficacy studies within the area of inflammatory diseases. NW is employed by Redoxis AB; and Redoxis AB is a service provider selling in vivo studies within the area of autoimmunity and inflammation., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

In recent years tremendous progress has been made in the therapeutic management of rheumatoid arthritis. Rheumatologists now have a large armamentarium of highly efficient drugs with different mechanisms of action at their disposal. These new drugs consist of biologicals (biological disease-modifying antirheumatic drugs, bDMARDs) as well as targeted synthetic DMARDs (tsDMARD). A common feature of these new drugs for treatment of rheumatoid arthritis is that the molecular target of the drug is known, which is not the case for conventional DMARDs. With the help of the new drugs, the therapeutic goal of inducing remission in patients with rheumatoid arthritis has become reality for many patients. Nevertheless, there is still a significant proportion of patients who do not adequately respond to all available drugs, leaving room for still further improvement. This review gives a short overview on the currently available and effective substances for the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease, characterized by synovial infiltration of various inflammatory cells. Chemokines are involved in controlling the recruitment of different cell types into the synovial membrane. The role of CCR6 in the development of arthritis so far remains unclear. In this study, we investigated the role of CCR6 in the pathogenesis of arthritis using three different murine arthritis models. Compared to WT animals, CCR6 -/- mice developed less clinical signs of arthritis in the collagen-induced arthritis model but not in the K/BxN serum transfer arthritis model and in the human tumour necrosis factor transgenic arthritis model, suggesting a defect in adaptive effector functions but intact innate effector functions in the development of arthritis in CCR6 -/- animals. In line with this, anti-collagen antibody levels were significantly reduced in CCR6 -/- mice compared with WT mice. Moreover, we demonstrate enhanced osteoclastogenesis in vitro in CCR6 -/- mice compared with WT mice. However, we did not detect differences in bone mass under steady state conditions in vivo between WT and CCR6-deficient mice. These data suggest that CCR6 is crucially involved in adaptive but not in innate immunity-driven arthritis. CCR6 or its chemokine ligand CCL20 might represent a possible new target for the treatment of RA., (© 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objectives: Bone destruction in rheumatoid arthritis is mediated by osteoclasts (OC), which are derived from precursor cells of the myeloid lineage. The role of the two monocyte subsets, classical monocytes (expressing CD115, Ly6C and CCR2) and non-classical monocytes (which are CD115 positive, but low in Ly6C and CCR2), in serving as precursors for OC in arthritis is still elusive., Methods: We investigated CCR2 -/- mice, which lack circulating classical monocytes, crossed into hTNFtg mice for the extent of joint damage. We analysed monocyte subsets in hTNFtg and K/BxN serum transfer arthritis by flow cytometry. We sorted monocyte subsets and analysed their potential to differentiate into OC and their transcriptional response in response to RANKL by RNA sequencing. With these data, we performed a gene ontology enrichment analysis and gene set enrichment analysis., Results: We show that in hTNFtg arthritis local bone erosion and OC generation are even enhanced in the absence of CCR2. We further show the numbers of non-classical monocytes in blood are elevated and are significantly correlated with histological signs of joint destruction. Sorted non-classical monocytes display an increased capacity to differentiate into OCs. This is associated with an increased expression of signal transduction components of RANK, most importantly TRAF6, leading to an increased responsiveness to RANKL., Conclusion: Therefore, non-classical monocytes are pivotal cells in arthritis tissue damage and a possible target for therapeutically intervention for the prevention of inflammatory joint damage., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

If misregulated, macrophage (Mϕ)-T cell interactions can drive chronic inflammation thereby causing diseases, such as rheumatoid arthritis (RA). We report that in a proinflammatory environment, granulocyte-Mϕ (GM-CSF)- and Mϕ colony-stimulating factor (M-CSF)-dependent Mϕs have dichotomous effects on T cell activity. While GM-CSF-dependent Mϕs show a highly stimulatory activity typical for M1 Mϕs, M-CSF-dependent Mϕs, marked by folate receptor β (FRβ), adopt an immunosuppressive M2 phenotype. We find the latter to be caused by the purinergic pathway that directs release of extracellular ATP and its conversion to immunosuppressive adenosine by co-expressed CD39 and CD73. Since we observed a misbalance between immunosuppressive and immunostimulatory Mϕs in human and murine arthritic joints, we devised a new strategy for RA treatment based on targeted delivery of a novel methotrexate (MTX) formulation to the immunosuppressive FRβ + CD39 + CD73 + Mϕs, which boosts adenosine production and curtails the dominance of proinflammatory Mϕs. In contrast to untargeted MTX, this approach leads to potent alleviation of inflammation in the murine arthritis model. In conclusion, we define the Mϕ extracellular purine metabolism as a novel checkpoint in Mϕ cell fate decision-making and an attractive target to control pathological Mϕs in immune-mediated diseases.

Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are the most commonly used diagnostic markers of rheumatoid arthritis (RA). These antibodies are predominantly of the immunoglobulin (Ig) M (RF) or IgG (ACPA) isotype. Other subtypes of both antibodies-particularly IgA isotypes and other autoantibodies-such as RA33 antibodies-have been repeatedly reported but their diagnostic value has still not been fully elucidated. Here, we investigated the prevalence of IgA, IgG, and IgM subtypes of RF, ACPA, and RA33 antibodies in patients with RA. To determine the diagnostic specificity and sensitivity sera from 290 RA patients (165 early and 125 established disease), 261 disease controls and 100 healthy subjects were tested for the presence of IgA, IgG, and IgM isotypes of RF, ACPA, and RA33 by EliA™ platform (Phadia AB, Uppsala, Sweden). The most specific antibodies were IgG-ACPA, IgA-ACPA, and IgG-RF showing specificities >98%, closely followed by IgG- and IgA-RA33 while IgM subtypes were somewhat less specific, ranging from 95.8% (RA33) to 90% (RF). On the other hand, IgM-RF was the most sensitive subtype (65%) followed by IgG-ACPA (59.5%) and IgA-RF (50.7%). Other subtypes were less sensitive ranging from 35 (IgA-ACPA) to 6% (IgA-RA33). RA33 antibodies as well as IgA-RF and IgA-ACPA were found to increase the diagnostic sensitivity of serological testing since they were detected also in seronegative patients reducing their number from 109 to 85. Moreover, analyzing IgM-RF by EliA™ proved more sensitive than measuring RF by nephelometry and further reduced the number of seronegative patients to 76 individuals. Importantly, among antibody positive individuals, RA patients were found having significantly more antibodies (≥3) than disease controls which generally showed one or two antibody species. Thus, increasing the number of autoantibodies in serological routine testing provides valuable additional information allowing to better distinguish between RA and other rheumatic disorders, also in patients not showing antibodies in current routine diagnostics. In conclusion, testing for multiple autoantibody specificities increases the diagnostic power of autoimmune diagnostics and could further support physicians in clinical decision-making.

Objective: The role of plasmacytoid dendritic cells (PDCs) and type I interferons (IFNs) in rheumatoid arthritis (RA) remains a subject of controversy. This study was undertaken to explore the contribution of PDCs and type I IFNs to RA pathogenesis using various animal models of PDC depletion and to monitor the effect of localized PDC recruitment and activation on joint inflammation and bone damage., Methods: Mice with K/BxN serum-induced arthritis, collagen-induced arthritis, and human tumor necrosis factor transgene insertion were studied. Symptoms were evaluated by visual scoring, quantification of paw swelling, determination of cytokine levels by enzyme-linked immunosorbent assay, and histologic analysis. Imiquimod-dependent therapeutic effects were monitored by transcriptome analysis (using quantitative reverse transcriptase-polymerase chain reaction) and flow cytometric analysis of the periarticular tissue., Results: PDC-deficient mice showed exacerbation of inflammatory and arthritis symptoms after arthritogenic serum transfer. In contrast, enhancing PDC recruitment and activation to arthritic joints by topical application of the Toll-like receptor 7 (TLR-7) agonist imiquimod significantly ameliorated arthritis in various mouse models. Imiquimod induced an IFN signature and led to reduced infiltration of inflammatory cells., Conclusion: The therapeutic effects of imiquimod on joint inflammation and bone destruction are dependent on TLR-7 sensing by PDCs and type I IFN signaling. Our findings indicate that local recruitment and activation of PDCs represents an attractive therapeutic opportunity for RA patients., (© 2017, American College of Rheumatology.)

The checkpoints and mechanisms that contribute to autoantibody-driven disease are as yet incompletely understood. Here we identified the axis of interleukin 23 (IL-23) and the T H 17 subset of helper T cells as a decisive factor that controlled the intrinsic inflammatory activity of autoantibodies and triggered the clinical onset of autoimmune arthritis. By instructing B cells in an IL-22- and IL-21-dependent manner, T H 17 cells regulated the expression of β-galactoside α2,6-sialyltransferase 1 in newly differentiating antibody-producing cells and determined the glycosylation profile and activity of immunoglobulin G (IgG) produced by the plasma cells that subsequently emerged. Asymptomatic humans with rheumatoid arthritis (RA)-specific autoantibodies showed identical changes in the activity and glycosylation of autoreactive IgG antibodies before shifting to the inflammatory phase of RA; thus, our results identify an IL-23-T H 17 cell-dependent pathway that controls autoantibody activity and unmasks a preexisting breach in immunotolerance., Competing Interests: The authors declare no competing financial interests.

Objective: While the regulatory role of individual microRNAs (miRNAs) in rheumatoid arthritis (RA) is well established, the role of DICER1 in the pathogenesis of the disease has not yet been investigated. The purpose of this study was to analyze the expression of factors involved in miRNA biogenesis in fibroblast-like synoviocytes (FLS) from RA patients and to monitor the arthritis triggered by K/BxN serum transfer in mice deficient in the Dicer gene (Dicer(d/d) )., Methods: The expression of genes and precursor miRNAs was quantified by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). MicroRNA macroarray profiling was monitored by qRT-PCR. Cytokines were quantified by enzyme-linked immunosorbent assay. Experimental arthritis in mice was achieved by the transfer of serum from K/BxN donors. Apoptosis was quantified using an enzyme-linked immunosorbent assay., Results: We found decreased DICER1 and mature miRNA expression in synovial fibroblasts from RA patients. These cells were hyperresponsive to lipopolysaccharide, as evidenced by their increased interleukin-6 secretion upon stimulation. Experimental serum-transfer arthritis in Dicer(d/d) mice confirmed that an unbalanced biogenesis of miRNAs correlated with an enhanced inflammatory response. Synoviocytes from both RA patients and Dicer(d/d) mice exhibited increased resistance to apoptotic stimuli., Conclusion: The findings of this study further substantiate the important role of DICER1 in the maintenance of homeostasis and the regulation of inflammatory responses., (© 2016, American College of Rheumatology.)

Objective: Abatacept (CTLA-4Ig) blocks CD28-mediated T cell activation by binding to the costimulatory B7 ligands CD80/CD86 on antigen presenting cells. Costimulatory molecules, however, can also be expressed on T cells upon activation. Therefore, the aim of our study was to investigate direct effects of CTLA-4Ig on distinct T cell subsets in RA patients., Methods: Phenotypic and functional analyses of CD4(+) T cells, including CD4(+) FoxP3(+) CD25(+) regulatory T cells (Treg), from RA patients were performed before and during CTLA-4Ig therapy. In addition T cells from healthy volunteers were analysed on in vitro culture with CTLA-4Ig or anti-CD80 and anti-CD86 antibodies. Apoptotic DNA fragmentation in CD4(+) and CD4(+) FoxP3(+) T cells was measured by TUNEL staining., Results: We observed an increase in T cells, including Treg cells, after initiation of CTLA-4Ig therapy, which was linked to a downregulation of activation-associated marker molecules and CD95 on CD4(+) T cells and Treg cells. CTLA-4Ig decreased CD95-mediated cell death in vitro in a dose-dependent manner. Functional analysis of isolated Treg cells from RA patients further revealed a diminished suppression of responder T cell proliferation. This was found to be due to CTLA-4Ig-mediated blocking of CD80 and CD86 on responder T cells that led to a diminished susceptibility for Treg cell suppression., Conclusion: CTLA-4Ig therapy in RA patients exerts effects beyond the suppression of T cell activation, which has to be taken into account as an additional mechanism of CTLA-4Ig treatment., (© The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: To investigate how tumor necrosis factor (TNF)-inhibiting therapy affects bone destruction and inflammation in a TNF-driven mouse model of rheumatoid arthritis., Methods: In order to evaluate the influence of TNF on osteoclastogenesis in vitro, different concentrations of TNF were added to spleen cell-derived monocytes in the absence or presence of different concentrations of RANKL. In addition, the effects of TNF inhibition on osteoclast precursors as well as local bone destruction in vivo were assessed by treating TNF-transgenic mice with different doses of adalimumab., Results: TNF stimulated osteoclastogenesis mainly by increasing the number of osteoclast precursor cells in vitro. This TNF effect was independent of the presence of RANKL. In the hTNF-transgenic mouse model of destructive arthritis, low-dose TNF-inhibiting therapy with adalimumab had no effect on synovial inflammation but significantly inhibited local bone destruction and the generation of osteoclasts. This inhibition was accompanied by a reduction in the number of c-Fms-positive osteoclast precursor cells in the bone marrow and a reduction of the osteoclast precursor pools in the blood and inflamed synovial membrane of hTNF-transgenic mice., Conclusion: Low-dose TNF-inhibiting therapy significantly reduces bone erosions by reducing the number of circulating and joint-invading osteoclast precursors. This effect is uncoupled from its antiinflammatory action., (Copyright © 2013 by the American College of Rheumatology.)

Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that signals through two distinct receptors, TNFR1 and TNFR2. TNF is essentially involved in the pathogenesis of various inflammatory and autoimmune diseases. Blocking TNF, in turn, has been proven to be highly effective in treating a variety of diseases. However, the role of its two receptors in these conditions is not very well understood. It is established that TNFR1 is mainly responsible for the detrimental effects of TNF. However, accumulating evidence suggests differential or even opposing effects of TNFR2 in the pathogenesis of a number of inflammatory and autoimmune conditions. In this review, we summarize the available data concerning biological and functional properties of the two TNF receptors and potential therapeutic consequences of these insights.

Objective: Both type I interferons (IFNα and IFNβ) and type II IFN (IFNγ) signal via pSTAT-1. Immunohistochemistry and the gene expression signatures of rheumatoid arthritis (RA) synovial tissue suggest an activated IFN/STAT-1 signaling pathway. The aim of this study was to determine the systemic activity of the IFN/STAT-1 signaling pathway in the peripheral blood cells of patients with RA., Methods: Fluorocytometry or quantitative polymerase chain reaction was used to measure the expression of STAT-1, pSTAT-1, and IFN-inducible genes (monokine induced by interferon-γ [MIG], interferon-γ-inducible protein 10 [IP-10], and 2',5'-oligoadenylate synthetase [OAS]) in the peripheral blood mononuclear cells (PBMCs) and purified CD14+ peripheral blood monocytes of patients with RA and healthy control subjects. PBMCs were also incubated for 48 hours with IFNs and several other cytokines to investigate influences on STAT-1 levels. To examine the significance of STAT-1 activation in RA monocytes after stimulation with IFNγ, the expression of pSTAT-1 and of the IFNγ-inducible chemokine MIG was measured using fluorocytometry., Results: Levels of STAT-1 were significantly increased in peripheral lymphocytes and monocytes from patients with RA compared with those from healthy control subjects. STAT-1 levels correlated well with RA disease activity, as measured by the Disease Activity Score in 28 joints and the Clinical Disease Activity Index. Furthermore, STAT-1 messenger RNA expression in RA CD14+ monocytes correlated with the expression of other IFN-target genes, such as IP-10, OAS, or MIG. In RA PBMCs, STAT-1 expression was increased not only by IFNs but also by tumor necrosis factor. RA monocytes demonstrated a considerably higher increase in pSTAT-1 and MIG levels upon IFNγ stimulation when compared with monocytes from control subjects, indicating that RA monocytes are more sensitive to IFNγ stimulation., Conclusion: In addition to supporting the role of IFNs in systemic proinflammatory activity, the results of this study further suggest preactivation of the IFNγ/STAT-1 signaling pathway, especially in RA monocytes., (Copyright © 2012 by the American College of Rheumatology.)

Objective: To investigate the mechanisms leading to the influx of inflammatory hematopoietic cells into the synovial membrane and the role of tumor necrosis factor receptor I (TNFRI) and TNFRII in this process in an animal model of rheumatoid arthritis (RA)., Methods: We performed bone marrow transplantations in human TNF-transgenic mice using hematopoietic cells from wild-type, TNFRI(-/-), TNFRII(-/-), and TNFRI/II(-/-) mice as donors and assessed the severity of arthritis histologically. Generation of osteoclasts from the different genotypes was analyzed in vitro and in vivo. Apoptosis was analyzed using annexin V staining as well as TUNEL assays., Results: Despite lacking responsiveness to TNF in their hematopoietic compartment, mice not only developed full-blown erosive arthritis but even showed increased joint destruction when compared with mice with a TNF-responsive hematopoietic compartment. We demonstrated different roles of the 2 different TNFRs in the regulation of these processes. The absence of TNFRI on hematopoietic cells did not affect joint inflammation but markedly attenuated erosive bone destruction via reduced synovial accumulation of osteoclast precursors. In contrast, the absence of TNFRII on hematopoietic cells increased joint inflammation as well as erosive bone destruction via the regulation of osteoclast precursor apoptosis., Conclusion: Our findings indicate that selective blockade of TNFRI, leaving the antiinflammatory effects of TNFRII unaltered instead of unselectively blocking TNF, might be advantageous in patients with RA.