Risk of cardiovascular comorbidities before and after the onset of rheumatic diseases.

OBJECTIVES: To elucidate the risk and temporal relationship of cardiovascular (CV) comorbidities in rheumatic diseases. METHODS: Patients in the FinnGen study diagnosed between 2000 and 2014 with seropositive (n = 2368) or seronegative (n = 916) rheumatoid arthritis (RA), ankylosing spondylitis (AS, n = 715), psoriatic arthritis (PsA, n = 923), systemic lupus erythematosus (SLE, n = 190), primary Sjogren's syndrome (pSS, n = 412) or gout (n = 2034) were identified from healthcare registries. Each patient was matched based on age, sex, and birth region with twenty controls without any rheumatic conditions. Overall risk ratios (RR) were calculated by comparing the prevalence of seven CV diseases between patients and controls. Logistic regression models were used for estimating odds ratios (OR) for CV comorbidities before and after the onset of rheumatic diseases. RESULTS: The RR for 'any CVD' varied from 1.14 (95 % confidence interval [CI] 1.02-1.26) in PsA to 2.05 (95 % CI 1.67-2.52) in SLE. Patients with SLE or gout demonstrated over two-fold risks for several CV comorbidities. Among CV comorbidities, venous thromboembolism (VTE) showed the highest effect sizes in several rheumatic diseases. The ORs for CV comorbidities were highest within one year before and/or after the onset of the rheumatic disease. However, in gout the excess risk of CV disease was especially high before gout diagnosis. CONCLUSIONS: The risk of CV comorbidities was elevated in all studied rheumatic diseases, with highest risks observed in SLE and gout. The risk for CV diseases was highest immediately before and/or after rheumatic disease diagnosis, highlighting the increased risk for CV comorbidities across all rheumatic diseases very early on the disease course.

Differences in JAK Isoform Selectivity Among Different Types of JAK Inhibitors Evaluated for Rheumatic Diseases Through In Vitro Profiling.

OBJECTIVE: The selectivity of JAK inhibitors (Jakinibs) forms the basis for understanding their clinical characteristics; however, evaluation of selectivity is hampered by the lack of comprehensive head-to-head studies. Our objective was to profile in parallel Jakinibs indicated or evaluated for rheumatic diseases for their JAK and cytokine selectivity in vitro. METHODS: We analyzed 10 Jakinibs for JAK isoform selectivity by assaying their inhibition of JAK kinase activity, binding to kinase and pseudokinase domains, and inhibition of cytokine signaling using blood samples from healthy volunteers and using isolated peripheral blood mononuclear cells (PBMCs) from patients with rheumatoid arthritis and from healthy donors. RESULTS: Pan-Jakinibs effectively suppressed kinase activity of 2 to 3 JAK family members, whereas isoform-targeted Jakinibs possessed varying degrees of selectivity for 1 or 2 JAK family members. In human leukocytes, Jakinibs predominantly inhibited the JAK1-dependent cytokines interleukin-2 (IL-2), IL-6, and interferons (IFNs). In PBMCs from patients with rheumatoid arthritis compared with healthy controls, inhibition of these cytokines was more pronounced, and some cell-type and STAT isoform differences were observed. Novel Jakinibs demonstrated high selectivity: the covalent Jakinib ritlecitinib showed 900- to 2,500-fold selectivity for JAK3 over other JAKs and specific suppression of IL-2-signaling, whereas the allosteric TYK2 inhibitor deucravacitinib inhibited IFNα signaling with high specificity. Interestingly, deucravacitinib targeted the regulatory pseudokinase domain and did not affect JAK in vitro kinase activity. CONCLUSION: Inhibition of JAK kinase activity did not directly translate into cellular inhibition of JAK/STAT signaling. Despite differences in JAK selectivity, the cytokine inhibition profiles of currently approved Jakinibs were highly similar, with preference for JAK1-mediated cytokines. Novel types of Jakinibs showed narrow cytokine inhibition profile specific for JAK3- or TYK2-mediated signaling.

Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors: a Nordic cohort study.

OBJECTIVES: To evaluate the risk of haematological malignancies in patients with psoriatic arthritis (PsA) overall, and in relation to treatment with tumour necrosis factor inhibitors (TNFi). METHODS: We identified that patients with PsA starting a first TNFi from the clinical rheumatology registers (CRR) in the five Nordic countries (n=10 621) and biologics-naïve PsA patients from (1) the CRR (n=18 705) and (2) the national patient registers (NPR, n=27 286, Sweden and Denmark) from 2006 through 2019. For Sweden and Denmark, general population comparators were matched 5:1 to PsA patients on birth year, year at start of follow-up and sex. By linkage to the national cancer registers in all countries, we collected information on haematological malignancies overall, and categorised into lymphoid or myeloid types. We estimated incidence rate ratios (IRRs) with 95% CIs using modified Poisson regression for TNFi-treated versus biologics-naïve PsA patients and versus the general population adjusted for age, sex, calendar period and country. RESULTS: During 59 827 person-years, 40 haematological malignancies occurred among TNFi-treated patients with PsA resulting in a pooled IRR of 0.96 (0.68-1.35) versus biologics-naïve PsA from CRR and an IRR of 0.84 (0.64-1.10) versus biologics-naïve PsA from NPR. The IRR of haematological malignancies in PsA overall versus general population comparators was 1.35 (1.17-1.55). The estimates were largely similar for lymphoid and myeloid malignancies. CONCLUSIONS: Treatment with TNFi in patients with PsA was not associated with an increased incidence of haematological malignancies. Conversely, a moderately increased underlying risk was seen in patients with PsA compared with the general population.

Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response.

The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase-signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) >3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P < 0.001). Marked (>20%) and statistically significant (P < 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (>50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.

Gorham-Stout disease with life-threatening pleural effusion treated with a pleuro-peritoneal shunt: a case report.

Summary: Gorham-Stout disease (GSD) is a rare bone disease characterized by massive osteolysis and lymphatic proliferation. The origin of the condition is unknown, and no established treatment protocol exists. Massive pleural effusion is a frequent complication of GSD in the thoracic region. We present the case of a 23-year-old male with thoracic GSD, subsequent paraparesis, and life-threatening pleural effusion. The patient was managed by a multidisciplinary team with a good recovery. The pleural effusion was successfully treated with a pleuro-peritoneal shunt. This is the first report of the use of this mini-invasive technique in the management of pleural effusion related to GSD. Further, we present the potential role of interleukin-6 and bone resorption markers in the measurement of the disease activity. Learning points: Multidisciplinary approach is important in the management of rare and severe disorders such as Gorham-Stout disease. Pleuro-peritoneal shunting is a valuable option in the treatment of pleural effusion related to GSD. Interleukin-6 and bone resorption markers appear useful in measuring the disease activity of GSD.

Short interruptions of TNF-inhibitor treatment can be associated with treatment failure in patients with immune-mediated diseases.

INTRODUCTION: The prevalence of immune-mediated diseases has increased in the past decades and despite the use of biological treatments all patients do not achieve remission. The aim of this study was to characterise the reasons for short interruptions during treatment with two commonly used TNF-inhibitors infliximab and adalimumab and to analyse the possible effects of the interruptions on immunisation and switching the treatment. MATERIAL AND METHODS: This case-control study was based on retrospective analyses of patient records and a questionnaire survey to clinicians. A total of 370 patients (194 immunised cases and 172 non-immunised controls, 4 excluded) were enrolled from eight hospitals around Finland. Eleven different diagnoses were represented, and the largest patient groups were those with inflammatory bowel or rheumatic diseases. RESULTS: Treatment interruptions were associated with immunisation in patients using infliximab (p < .001) or adalimumab (p < .000001). Patients with treatment interruptions were more likely to have been treated with more than one biological agent compared to those without treatment interruptions. This was particularly prominent among patients with a rheumatic disease (p < .00001). The most frequent reason for a treatment interruption among the cases was an infection, whereas among the control patients it was remission. The median length of one interruption was one month (interquartile range 1-3 months). CONCLUSION: Our results suggest that the interruptions of the treatment with TNF-inhibitors expose patients to immunisation and increase the need for drug switching. These findings stress the importance of careful judgement of the need for a short interruption in the biological treatment in clinical work, especially during non-severe infections.

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

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

IRF2BP2 Mutation Is Associated with Increased STAT1 and STAT5 Activation in Two Family Members with Inflammatory Conditions and Lymphopenia.

Interferon regulatory factor 2 binding protein 2 (IRF2BP2) is a transcriptional coregulator that has an important role in the regulation of the immune response. IRF2BP2 has been associated with the Janus kinase (JAK)-signal transducers and activators of transcription (STAT) pathway, but its exact role remains elusive. Here, we identified a novel clinical variant, IRF2BP2 c.625_665del, from two members of a family with inflammatory conditions and investigated the function of IRF2BP2 and c.625_665del mutation in JAK-STAT pathway activation and inflammatory signaling. The levels of constitutive and cytokine-induced phosphorylation of STATs and total STAT1 in peripheral blood monocytes, T cells, and B cells from the patients and four healthy controls were measured by flow cytometry. Inflammation-related gene expression was studied in peripheral blood mononuclear cells using direct digital detection of mRNA (NanoString). Finally, we studied the relationship between IRF2BP2 and STAT1 activation using a luciferase reporter system in a cell model. Our results show that patients having the IRF2BP2 c.625_665del mutation presented overexpression of STAT1 protein and increased constitutive activation of STAT1. In addition, interferon-induced JAK-STAT signaling was upregulated, and several interferon-inducible genes were overexpressed. Constitutive phosphorylation of STAT5 was also found to be upregulated in CD4+ T cells from the patients. Using a cell model, we show that IRF2BP2 was needed to attenuate STAT1 transcriptional activity and that IRF2BP2 c.625_665del mutation failed in this. We conclude that IRF2BP2 has an important role in suppressing immune responses elicited by STAT1 and STAT5 and suggest that aberrations in IRF2BP2 can lead to abnormal function of intrinsic immunity.

Proprotein convertase enzyme FURIN is upregulated in primary Sjögren's syndrome.

OBJECTIVES: The proprotein convertase enzyme FURIN is a critical regulator of the anti-inflammatory TGFß-1 cytokine and peripheral immune tolerance. In T cells, FURIN is co-regulated with IFN-γ and thus highly expressed in T helper 1 type cells. Previous studies have demonstrated that FURIN is upregulated in inflammatory conditions, including atherosclerosis, rheumatoid arthritis and systemic lupus erythematosus. Here, we evaluated the levels of FURIN in the plasma and peripheral blood mononuclear cells (PBMCs) of patients with primary Sjögren's syndrome (pSS) and in healthy controls. METHODS: FURIN plasma levels were determined by ELISA, and the mRNA expression in PBMCs was quantitated using qPCR. FURIN levels in the plasma were correlated with the clinical and demographic characteristics of the patients. RESULTS: FURIN was found to be significantly upregulated at both the protein and mRNA level in pSS patients compared to healthy controls. In pSS patients, high FURIN protein levels were significantly associated with elevated IFN-γ levels in the plasma as well as a longer duration of sicca symptoms in the eyes. pSS patients with high FURIN levels in their plasma showed a trend towards lower levels of serum beta-2 microglobulin, ESR and a lower systemic disease activity index ESSDAI. CONCLUSIONS: The proprotein convertase FURIN is significantly upregulated in pSS. Elevated FURIN levels associate with high levels of the Th1 type cytokine IFN-γ and long duration of dry eye symptoms. Patients with high FURIN levels show signs of lower disease activity suggesting that FURIN might have a protective role in pSS.

Efficacy and effectiveness of tumour necrosis factor inhibitors in the treatment of rheumatoid arthritis in randomized controlled trials and routine clinical practice.

Objective: Efficacy of TNF inhibitors in the treatment of RA assessed in randomized controlled trials (RCTs) may not be fully comparable to routine care owing to the stringent inclusion criteria. The objective of this study was to observe the effectiveness of TNF inhibitors in real-world patients and assess the patients' potential eligibility for the RCTs. Methods: RA patients starting a TNF-inhibitor treatment between 2004 and 2014 were identified from the National Register for Biologic Treatment in Finland, which is a longitudinal observational cohort study. Effectiveness was measured using the ACR and EULAR response criteria and by studying the proportion of patients reaching DAS28 remission. The patients' baseline characteristics were compared against the inclusion criteria of 27 RCTs. Results: EULAR moderate and good treatment responses at 6 months were achieved by 69 and 40% of the users of the first TNF inhibitor, respectively. ACR20, ACR50 and ACR70 responses were reached by 48, 27 and 13%, respectively. DAS28 remission was reached by 47%. Only 7.6-44% of the patients would have been potentially eligible for the RCTs. The eligible patients had better treatment responses compared with the non-eligible patients. Different TNF inhibitors were mostly equipotent, but the usage of MTX co-therapy had a major influence on treatment response. Conclusion: Only a small proportion of patients would have been eligible for RCTs, and the efficacy of TNF inhibitors assessed in them cannot be generalized directly into Finnish routine health care.

Cytokine-induced STAT1 activation is increased in patients with primary Sjögren's syndrome.

Limited data are available regarding the intracellular responses to different cytokines in primary Sjögren's syndrome (pSS). We studied the signal transducer and activator of transcription (STAT) activation profile in response to cytokine stimulations in peripheral blood mononuclear cells (PBMCs) from pSS patients by multicolor flow cytometry. The expression of the suppressors of cytokine signaling (SOCS), and interferon (IFN)-γ target genes in PBMCs was studied using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The induction of STAT1 phosphorylation in response to stimulation with IFN-α, IFN-γ or interleukin (IL)-6 was significantly increased in B cells and monocytes from pSS patients. Accordingly, the STAT1-mediated gene responses were significantly enhanced in PBMCs from pSS patients. Finally, the expression of SOCS1 and SOCS3 mRNA was increased in pSS patients. The results indicate increased sensitivity of immune cells from pSS patients to STAT1-activating signals, and may partly explain the IFN signature observed in pSS.

[Exemplary cases of individualization of biological therapy]. / Esimerkkitapauksia biologisen hoidon yksilöllistämisestä.

The use of biological drugs consisting of large molecules has in recent years expanded to new indications and new specialties. These drugs are most commonly proteins possessing the structure of an antibody or a receptor, and treatment with them is significantly more expensive than that carried out with conventional small molecule drugs. Determination of drug levels and emerging antibodies form the basis of individualization. They will enable better treatment results with simultaneous avoidance of unnecessary medications, excessive doses--and extra costs. We demonstrate the individualization of TNF-α blocker therapy through patient cases in various situations.

The activity of JAK-STAT pathways in rheumatoid arthritis: constitutive activation of STAT3 correlates with interleukin 6 levels.

OBJECTIVE: Many cytokines involved in RA activate the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathways. Therapeutic drugs that inhibit these pathways are being developed for RA. To investigate disease-related alterations in the activity of JAK-STAT pathways in RA, we studied the expression and activation of STAT1 and STAT3 in unstimulated and cytokine-stimulated cells and determined the levels of circulating cytokines. METHODS: The expression of STAT1 and STAT3 mRNA in peripheral blood (PB) and SF T cells and monocytes was studied in RA patients and healthy volunteers by RT-PCR. Basal and cytokine (IFN-γ, IL-6, IL-10)-induced STAT phosphorylation was analysed in PB T cells and monocytes using multicolour flow cytometric analysis. RESULTS: STAT3 mRNA levels were up-regulated in both PB and SF T cells and monocytes from RA patients. STAT1 expression was elevated in SF monocytes. The levels of phospho-STAT3 in resting PB T cells and monocytes were significantly higher in patients with RA than in healthy volunteers. IL-6 levels were elevated in RA plasma and correlated with the level of STAT3 phosphorylation in CD4(+) T cells and monocytes. IL-6-mediated STAT3 activation was deregulated in T cells from RA patients. IL-6-induced phosphorylation of STAT3 was decreased in CD4(+) T cells from patients with high plasma IL-6 levels and constitutive STAT3 phosphorylation. CONCLUSION: The results suggest that IL-6 induces hyperactivation of STAT3 in circulating immune cells in active RA, and this subsequently desensitizes the IL-6 response in T cells.

Expression analysis of Tudor-SN protein in mouse tissues.

Tudor-SN (SND1, p100) has been shown to function as a transcriptional coactivator as well as a modulator of RNA metabolism and biogenesis and a component in the RNA-induced silencing complex (RISC). Tudor-SN consists of five repeats of staphylococcus nuclease-like domains (SN1-SN5) and, a Tudor domain implicated in binding to methylated ligands. The protein is highly conserved through evolution from fission yeast to mammals and it exists as a single gene without any close homologs. Tudor-SN is found to be overexpressed in several cancers such as colon adenocarcinomas and prostate cancer. The conservation of Tudor-SN along evolution suggests it may have important functions; however, the physiological function of Tudor-SN has not yet been characterized. In this study we analyzed the expression and localization of Tudor-SN in mouse tissues and organs by immunohistochemistry, fluorescent immunostaining, Western blotting and RT-qPCR. Expression analysis indicated that Tudor-SN is widely expressed in most organs with the exception of muscle cells. Up-regulated expression was observed in rapidly dividing cells and progenitor cells such as in spermatogonial cells in testis, in the follicular cells of ovary, in the cells of crypts of Lieberkühn of ileum and basal keratinocytes of skin and hair follicle when compared to more differentiated or terminally differentiated cells in the respective organs. Moreover, Tudor-SN was robustly expressed in T-cells and Tudor-SN was co-expressed with CD3 in T-cells in the Peyer's patch, spleen and lymph node. The wide expression pattern of Tudor-SN and high expression in proliferating and self-differentiating cells suggests that the protein serves functions related to activated state of cells.

Chronic back pain in patients with rheumatoid arthritis and in a control population: prevalence and disability--a 5-year follow-up.

OBJECTIVES: To determine the prevalence of chronic back pain and its changes over 5 years in patients with RA compared with community controls and to evaluate the influence of chronic back pain in functional capacity, general pain and global health. METHODS: The prevalence of chronic back pain in 1076 patients with RA and in 1491 community controls was evaluated using a mailed questionnaire, which also queried the functional capacity on the HAQ, and general pain and global health on visual analogue scales. RESULTS: Chronic back pain was more frequent in the general population than in patients with RA: 19% of patients with RA and 25% of controls reported chronic back pain (P < 0.001). After 5 years, 57% of these patients initally reporting pain and 58% of controls still reported chronic back pain. In community controls with and without chronic back pain, the median HAQ, general pain and global health were 0.13 vs 0.00, 28 vs 6 and 28 vs 11, respectively (P < 0.001). The figures were 0.88 vs 0.63 (P = 0.05), 42 vs 26 and 42 vs 30 (P < 0.001), respectively, in patients with RA. All analyses were adjusted for age and sex. CONCLUSION: Chronic back pain does not occur more frequently in patients with RA than in the general population. Almost 60% of patients and controls who reported chronic back pain still reported it 5 years later. In patients with RA and in the control population, subjects with chronic back pain had worse functional capacity, general pain and global health.

Expression of IL-10 family cytokines in rheumatoid arthritis: elevated levels of IL-19 in the joints.

OBJECTIVES: Interleukin (IL)-10 functions as an anti-inflammatory cytokine in rheumatoid arthritis (RA). New IL-10 family cytokines IL-19, IL-20, IL-22, IL-24, and IL-26 have recently been discovered. Information concerning the expression and function of these cytokines in autoimmune diseases is currently limited. The aim of this study was to investigate their expression in RA. METHODS: mRNA levels of the cytokines were studied using quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MCs), purified T cells, and monocytes/macrophages from RA patients and healthy volunteers, and synovial tissues from patients with RA or osteoarthritis (OA), were examined. The expression of IL-19 protein in T cells and monocytes/macrophages was studied by flow cytometry. RESULTS: IL-10 and IL-19 mRNA levels were significantly elevated in SFMCs from patients with RA compared with PBMCs from RA patients or healthy volunteers. IL-20 and IL-22 mRNA levels were also upregulated in RA SFMCs but their level of expression was lower than that of IL-10 or IL-19. Importantly, synovial tissue IL-19 levels in RA were increased when compared with OA. IL-19 expression was upregulated in both T cells and macrophages derived from patients with RA. IL-1beta increased IL-19 levels in PBMCs, suggesting that elevated levels of IL-1 in RA joints may contribute to upregulated IL-19 expression. CONCLUSIONS: The majority of the IL-10 family cytokines are expressed in RA. IL-19 demonstrated the highest expression in rheumatoid joints, and could thus be involved in the regulation of synovial inflammation in RA.

TCRzetadim lymphocytes define populations of circulating effector cells that migrate to inflamed tissues.

The T-cell receptor zeta (TCRzeta) chain is a master sensor and regulator of lymphocyte responses. Loss of TCRzeta expression has been documented in infectious, inflammatory, and malignant diseases, suggesting that it may serve to limit T-cell reactivity and effector responses at sites of tissue damage. These observations prompted us to explore the relationship between TCRzeta expression and effector function in T cells. We report here that TCRzeta(dim) lymphocytes are enriched for antigen-experienced cells refractory to TCR-induced proliferation. Compared to their TCRzeta(bright) counterparts, TCRzeta(dim) cells share characteristics of differentiated effector T cells but use accessory pathways for transducing signals for inflammatory cytokine gene expression and cell contact-dependent pathways to activate monocytes. TCRzeta(dim) T cells accumulate in inflamed tissues in vivo and have intrinsic migratory activity in vitro. Whilst blocking leukocyte trafficking with anti-TNF therapy in vivo is associated with the accumulation of TCRzeta(dim) T cells in peripheral blood, this T-cell subset retains the capacity to migrate in vitro. Taken together, the functional properties of TCRzeta(dim) T cells make them promising cellular targets for the treatment of chronic inflammatory disease.

Pathways of T cell activation and terminal differentiation in chronic inflammation.

Immune and inflammatory responses are governed by antigen-specific T cells, whose activation, differentiation and effector function are induced by signals delivered via the T cell antigen receptor (TCR) and by costimulatory and cytokine receptors. The molecular events leading to the activation of naïve T cells have been extensively studied and are well characterized. Much less is known about the molecular and biochemical events regulating the activation of T cells in chronic inflammatory diseases such as rheumatoid arthritis (RA). This review examines the current state of knowledge of T cell activation in chronic inflammation, focusing on RA, and summarizes experimental data which indicate that the chronic inflammatory process may profoundly affect TCR and cytokine signal transduction pathways. We present evidence suggesting that in chronic inflammation, the antigen-driven TCR-mediated processes are attenuated, while cytokine-driven effector responses are sustained or even enhanced. The possible implications of this inbalance are discussed.

T cell receptor zeta reconstitution fails to restore responses of T cells rendered hyporesponsive by tumor necrosis factor alpha.

Expression and function of the antigen T cell receptor (TCR) play a central role in regulating immune responsiveness. Accordingly, targeting the expression of TCRalphabeta or its associated CD3 subunits profoundly influences T cell development and adaptive immunity. Down-regulation of the invariant TCRzeta chain has been documented in a wide variety of chronic inflammatory and infectious diseases, and is thought to contribute to the paradoxical immune suppression observed in these diseases. Previously, we reported that prolonged exposure of T cell hybridoma clones to tumor necrosis factor alpha (TNF) induces nondeletional and reversible hyporesponsiveness to TCR engagement, associated with down-regulation of TCRzeta chain expression, impaired TCR/CD3 complex assembly, and attenuation of TCR-induced membrane proximal tyrosine phosphorylation. Here, we have tested whether receptor specific T cell responses are rescued in TNF-treated T cell hybridomas by retroviral-mediated expression of zeta-chimeric (C2zeta) receptors or wild-type TCRzeta. Expression of C2zeta receptors at the cell surface is relatively refractory to chronic TNF stimulation. However, C2zeta receptor function depends on association with endogenous TCRzeta chains, whose expression is down-regulated by TNF, and so C2 receptor specific responses are attenuated in TNF-treated T cells. Unexpectedly, overexpression of wild-type TCRzeta maintains cell surface TCR/CD3 complex expression but fails to rescue receptor proximal signaling in TNF-treated T cells, suggesting the existence of hitherto unrecognized mechanisms through which TNF regulates T cell responsiveness. We provide additional evidence that TNF also uncouples distal TCR signaling pathways independently of its effects on TCRzeta expression.

Early and extensive erosiveness in peripheral joints predicts atlantoaxial subluxations in patients with rheumatoid arthritis.

OBJECTIVE: To study the prevalence of cervical spine subluxations and predictive factors for atlantoaxial subluxations (including anterior atlantoaxial subluxation and atlantoaxial impaction, i.e., vertical subluxation) in patients with rheumatoid arthritis (RA) who were treated early and continuously with disease-modifying antirheumatic drugs for 8-13 years. METHODS: Radiographs of the cervical spine were obtained in 103 of 110 patients (the 110 surviving patients of the original 135-patient cohort) at their 8-13-year followup visits. The prevalence of cervical spine subluxations was determined. Demographic variables and the first 5-year serial data concerning disease course were analyzed in a logistic regression model to find predictive factors for atlantoaxial subluxations. RESULTS: Atlantoaxial subluxations were found in 14 patients (14%), and 5 patients (5%) had subaxial subluxations. Older age at baseline, greater disease activity during the first 5 years, and early erosiveness in peripheral joints predicted the development of atlantoaxial subluxations. Patients who had >or=10% of the maximum possible radiographic damage (by Larsen score) in peripheral joints at 5 years were 15.9 times more likely to develop atlantoaxial subluxations at 8-13 years than patients whose peripheral joint damage remained <10% of the maximum. CONCLUSION: Compared with historical control RA cohorts, a lower prevalence of cervical spine destruction was found in the present group of patients. Rapid erosiveness in peripheral joints was the best predictor for atlantoaxial subluxations. Extensive erosiveness in peripheral joints should alert rheumatologists to the possible development of atlantoaxial subluxations in patients with RA.