Macrophages in obesity are characterised by increased IL-1ß response to calcium-sensing receptor signals.

OBJECTIVE: Obesity is complicated by inflammatory activation of the innate immune system. Stimulation of the calcium-sensing receptor (CaSR) by extra-cellular calcium ions ([Ca2+]ex) can trigger NLRP3 inflammasome activation and inflammation. We hypothesised, that this mechanism might contribute to the activation of adipose tissue (AT) in obesity, and investigated [Ca2+]ex-induced, CaSR mediated IL-1ß release by macrophages in obesity. METHODS: [Ca2+]ex-induced IL-1ß release was investigated in monocyte-derived macrophages (MDM) generated from peripheral blood of patients with obesity and from normal-weight controls. Visceral and subcutaneous AT biosamples were stimulated with [Ca2+]ex, and IL-1ß release, as well as expression of NLRP3 inflammasome and cytokine genes, was determined. RESULTS: Both MDM and AT readily responded with concentration-dependent IL-1ß release already at low, near physiological concentrations to addition of [Ca2+]ex, which was more than 80 fold higher than the LPS-induced effect. IL-1ß levels induced by [Ca2+]ex were significantly higher not only in MDM from patients with obesity compared to controls, but also in visceral versus subcutaneous AT. This fat-depot difference was also reflected by mRNA expression levels of inflammasome and cytokine genes. CONCLUSIONS: Obesity renders macrophages more susceptible to [Ca2+]ex-induced IL-1ß release and pyroptosis. Increased susceptibility was independent of the response to LPS and circulating CRP arguing against mere pro-inflammatory pre-activation of monocytes. Instead, we propose that CaSR mediated signalling is relevant for the deleterious innate immune activation in obesity.

Humoral and cellular response to COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases under real-life conditions.

OBJECTIVES: Successful vaccination is key to overcoming the COVID-19 pandemic. Immunosuppressive medication is known to potentially compromise vaccination responses, and expansion of our knowledge on vaccination efficacy in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is therefore of utmost importance. METHODS: We conducted a single-centre observational study and evaluated the efficacy of approved COVID-19 vaccines in 303 adult AIIRD patients. Serum levels of IgG antibodies against the S1 subunit of SARS-CoV-2 spike proteins (anti-S IgG) were measured at least two weeks after vaccination. In a subgroup of patients without humoral response, T-cell responses were determined using an interferon-γ gamma release assay. RESULTS: Overall seropositivity rate was 78.5% and was significantly lower in patients under immunosuppressive therapy (75.7 vs 93.2%, P = 0.009). No difference regarding the vaccination type was observed. Glucocorticoids, mycophenolate-mofetil, TNF inhibitors, tocilizumab, abatacept and rituximab were all associated with non-response after proper vaccination. The risk was highest under RTX therapy (OR 0.004, 95% CI 0.001, 0.023, P < 0.0001). A strong negative correlation was observed between time since vaccination with an mRNA vaccine and anti-S antibody levels (r=-0.6149, P < 0.0001). In patients without humoral response, a T-cell response was found in 50%. CONCLUSIONS: COVID-19 vaccination in patients with AIIRD is effective using any approved vaccine. Humoral response might be impaired depending on the individual immunosuppressive medication. The risk of non-response is highest under rituximab therapy. Anti-S IgG antibody levels wane over time after mRNA vaccination. Importantly, 50% of humoral non-responders showed a T-cellular response, suggesting T-cell-mediated protection to a certain extent.

Expansion of CD4+CD8+ double-positive T cells in rheumatoid arthritis patients is associated with erosive disease.

OBJECTIVES: CD4+CD8+ double-positive (DP) T cells are expanded in the peripheral blood of a subset of patients with RA. This study examines the clinical significance of DP T cells in RA. METHODS: In 70 RA patients, DP T cells were measured by flow cytometry. Clinical data were obtained, and hand and feet radiographs were scored according to the Sharp/van der Heijde (SvdH) method. The association between DP T cell frequency and erosive joint destruction was analysed by correlation and multiple logistic regression analysis. RESULTS: Nineteen RA patients (27.1%) displayed increased DP T cell frequencies, which correlated with age (r = 0.288, P =0.016). Expansion of DP T cells was associated with the occurrence of erosions (94,7% vs 43,1%, P <0.001), with a higher SvdH joint damage score (24.5 vs 6, P =0.008) and with more frequent use of biologic or targeted-synthetic DMARDs (68.4% vs 38%, P =0.02). In patients with non-erosive disease, DP T cell frequencies correlated with the joint space narrowing score (n = 28, r = 0.44, P =0.02). Logistic regression revealed DP T cells to be associated with erosive disease (OR 1.90, P <0.05). CONCLUSION: Expansion of DP T cells is associated with joint damage and frequent escalation of therapy, possibly suggesting a contribution to more severe RA.

[Recommendations of the German Society for Rheumatology for management of patients with inflammatory rheumatic diseases in the context of the SARS-CoV-2/COVID-19 pandemic - Update July 2020]. / Handlungsempfehlungen der Deutschen Gesellschaft für Rheumatologie e. V. für die Betreuung von Patienten mit entzündlich rheumatischen Erkrankungen im Rahmen der SARS-CoV-2/COVID-19-Pandemie ­ Update Juli 2020.

A few days after the SARS-CoV-2 infection was declared a pandemic, the German Society for Rheumatology (DGRh) compiled first recommendations for the care of patients with inflammatory rheumatic diseases (IRD). These first recommendations were based on an expert consensus and were largely non-evidence-based. Now that the first scientific data from registers, cross-sectional studies, case reports and case series are available, the present update is intended to update the previous recommendations and to add new findings. The current recommendations are based on a literature search of publications available up to 15 June 2020 and address preventive measures (such as hygiene measures or vaccinations) and the use of immunomodulatory/immunosuppressive drugs. An important goal of the current recommendations is also to prevent harm to patients with IRD through unjustified restriction of care. The DGRh will continue to update its recommendations in the case of new aspects and will publish them as well as further information on the COVID-19 pandemic on its homepage ( www.dgrh.de ) in an ongoing process.

PIR-B expressing CD8+ T cells exhibit features of Tc1 and Tc17 in SKG mice.

OBJECTIVE: In autoimmune arthritis, TCR signalling is attenuated by peripheral tolerance mechanisms. We have described previously a population of inhibitory receptor LIR-1 expressing autoreactive CD8+ T cells in rheumatoid arthritis. Here, we investigated the role of CD8+ T cells in murine autoimmune arthritis by analysing their expression of the mouse orthologue of LIR-1, PIR-B. METHODS: Frequencies of PIR-B+CD8+ T cells were determined in the SKG arthritis model. The phenotype of those cells was determined ex vivo by FACS and functionality was investigated by means of cytokine production and cytolytic potential upon activation in vitro. RESULTS: SKG mice, under non-SPF (specific pathogen-free) conditions with clinical symptoms of arthritis, were found to harbour significantly increased frequencies of PIR-B+CD8+ T cells. Those cells showed a pro-inflammatory phenotype with preferential production of IL-17 and IFN-γ. The frequency of those cells correlated inversely with the arthritis score, indicating that they might represent autoreactive, but functionally inhibited, CD8+ T cells. CONCLUSION: PIR-B+CD8+ T cells from SKG mice show a cytotoxic and pro-inflammatory phenotype. Inhibition of CD8+ T cell autoreactivity by PIR-B/LIR-1 receptor signalling might be a counter-regulatory mechanism to curb autoreactivity and arthritis.

Autoimmune arthritis induces paired immunoglobulin-like receptor B expression on CD4+ T cells from SKG mice.

The chronic, destructive autoimmune arthritis in SKG mice, which closely resembles human rheumatoid arthritis, is the result of self-reactive T cells escaping thymic deletion. Since the inhibitory receptor LIR-1 is up-regulated on auto-reactive T cells in human rheumatoid arthritis, the role of its murine ortholog PIR-B was investigated. Peripheral CD4+ T cells from SKG mice were found to frequently express PIR-B, and this population produces more frequently IL-17 upon in vitro stimulation compared to PIR-B- cells. A much larger fraction of PIR-B+ T cells, however, was found to secret no IL-17, but IFN-γ. With regards to the clinical course of the disease, high frequencies of PIR-B+ CD4+ T cells were found to be associated with a milder course of arthritis, suggesting that the net effect of PIR-B expression is suppression of autoreactive T cells. Our results indicate that overexpression of PIR-B on IL-17-producing SKG CD4+ T cells might represent an effective counter-regulatory mechanism against the destructive potential of those cells. More importantly, a major population of PIR-B+ T cells in SKG mice appears to play an inhibitory role by way of their IFN-γ production, since high frequencies of those cells ameliorate the disease.

In vitro response pattern of monocytes after tmTNF reverse signaling predicts response to anti-TNF therapy in rheumatoid arthritis.

BACKGROUND: Treatment with TNF inhibitors is very efficient in the majority of the patients with rheumatoid arthritis (RA), but it does not achieve a sufficient treatment response in 40-50% of the cases. Goal of the study was to assess functional ex vivo-tests of RA monocytes as prognostic parameters of the subsequent treatment response. METHODS: 20 anti-TNF naïve RA patients were enrolled in a prospective, open-label trial, and Etanercept therapy was initiated. Prior to treatment, reverse signaling was induced in peripheral blood monocytes by tmTNF crosslinking via TNFR2:Ig construct Etanercept in a standardized ex vivo-assay. Released cytokine and cytokine receptor concentrations were determined as parameters of the monocyte response. RESULTS: Crosslinking of tmTNF and consecutive reverse signaling led to production of pro- and anti-inflammatory cytokines and of soluble cytokine decoy receptors such as sTNFR1 and sIL-1R2. Several of the measured concentrations were found to correlate with the treatment response according to the EULAR criteria. The correlation was most pronounced in sTNFR1 concentrations (r = -0.657, p = 0.0031), which also predicted a good clinical response with the highest sensitivity and specificity according to EULAR criteria. CONCLUSIONS: Herein we propose that the tmTNF crosslinking-triggered shedding of soluble decoy receptors and production of anti-inflammatory cytokines could contribute to the clinical efficacy of TNF inhibitors, and that in vitro quantification of this secretion by RA monocytes prior to treatment can be used to predict the clinical response. Further development of such standardized tests could be a step towards personalized medicine by providing rheumatologists with a rational choice for first line biological therapy in patients with RA.

Searching for inhibition of return in the rat using the covert orienting of attention task.

Inhibition of return (IOR) is an important psychological construct describing inhibited responses to previously attended locations. In humans, it is investigated using Posner's cueing paradigm. This paradigm requires central visual fixation and detection of cued stimuli to the left or right of the fixation point. Stimuli can be validly or invalidly cued, appearing in the same or opposite location to the cue. Although a rat version of the spatial cueing paradigm (the covert orienting of attention task) does exist, IOR has so far not been demonstrated. We therefore investigated whether IOR could be robustly demonstrated in adult male rats using the covert orienting of attention task. This task is conducted in holed wall operant chambers with the central three holes mimicking the set-up for Posner cueing. Across four samples of rats (overall n = 84), we manipulated the following task parameters: stimulus onset asynchronies (Experiments 1-3), cue brightness (Experiment 1b) and the presence of a central reorienting event (Experiment 4). In Experiment 1, we also investigated strain differences by comparing Lister Hooded rats to Sprague-Dawley rats. Although Lister Hooded rats briefly showed evidence of IOR (Experiment 1a, and see Online Resource 1 data), we were unable to replicate this finding in our other experiments using different samples of this strain. Taken together, our findings suggest that IOR cannot be robustly demonstrated in the rat using the covert orienting of attention task conducted in holed wall operant chambers.

Brief report: deficient thymic output in rheumatoid arthritis despite abundance of prethymic progenitors.

OBJECTIVE: To determine the frequencies of common lymphoid progenitors (CLPs) and recent thymic emigrants (RTEs) in patients with rheumatoid arthritis (RA) and healthy control subjects. METHODS: Flow cytometry was performed to determine the frequencies of CLPs and RTEs in the peripheral blood of 101 control subjects and 51 patients with RA. Thirteen of these patients were also analyzed longitudinally for 6 months after initiation of treatment with a tumor necrosis factor (TNF) inhibitor. RESULTS: A significant correlation between the frequencies of CLPs and RTEs was observed in healthy control subjects. The frequencies of both CLPs and RTEs decreased with age and correlated inversely with absolute lymphocyte numbers in peripheral blood. In patients with RA, the frequencies of RTEs were significantly decreased compared with the frequencies in control subjects. Importantly, the frequencies of CLPs were significantly higher in patients with RA compared with control subjects. Therapeutic TNF blockade further increased the frequency of CLPs, thereby normalizing thymic output, as indicated by an increase in the number of RTEs. CONCLUSION: Thymic insufficiency in RA is not attributable to an inadequate supply of progenitor cells to the thymus. Thus, insufficient numbers of RTEs could result from inadequate thymic T cell neogenesis, or alternatively, could be a consequence of high CD4+ T cell turnover, homeostatic proliferation, and subsequent dilution of the RTE population.

Tumor necrosis factor receptor type I expression of CD4+ T cells in rheumatoid arthritis enables them to follow tumor necrosis factor gradients into the rheumatoid synovium.

OBJECTIVE: The cytokine tumor necrosis factor (TNF) plays a central role in the pathogenesis of rheumatoid arthritis (RA), but its disease-specific effector mechanisms have not been fully elucidated. This study was undertaken to investigate the role of TNF in T cell accumulation and migration in the synovitic joints of RA patients. METHODS: Vital tissue sections from rheumatoid synovium were generated using a horizontally oscillating microtome and were coincubated with fluorescence-labeled CD4+ T cells. Migration was detected by fluorescence and confocal microscopy. Migrating T cells were recovered from the tissue and analyzed for phenotype. Chemotaxis of CD4+ T cells from RA patients in response to increasing concentrations of TNF was analyzed in Transwell experiments. RESULTS: CD4+ T cells from RA patients migrated into the tissue sections in significantly higher numbers than T cells from healthy controls. Migrating CD4+ T cells differed from nonmigrating ones in their increased expression of TNF receptor type I (TNFRI), which was expressed on a fraction of circulating CD4+ T cells from RA patients, but not from controls. CD4+ T cells from the peripheral blood of RA patients were also found to migrate along TNF concentration gradients ex vivo. Accordingly, blockade of either TNF or TNFRI nearly abrogated in vitro T cell migration in synovial tissue. CONCLUSION: Our findings indicate that the interaction of TNF with TNFRI is pivotal for T cell migration in synovial tissue in vitro, and thereby suggest a relevant role of the cytokine for in vivo T cell trafficking to synovitic joints.

Efficacy and NSAID-sparing effect of secukinumab 150 mg in ankylosing spondylitis: results from phase IV ASTRUM study.

Background: Radiographic axial spondyloarthritis (r-axSpA), formerly known as ankylosing spondylitis (AS), is a chronic, inflammatory rheumatic disease associated with symptoms such as inflammatory back pain, morning stiffness, and arthritis. First-line recommendations for patients with AS include treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) for reducing pain and stiffness. Objectives: The objective of our study is to evaluate the efficacy and short-term NSAID-sparing effect of secukinumab in patients with AS currently treated with NSAIDs. Design: We assessed the clinical Assessment of SpondyloArthritis International Society (ASAS20) response to secukinumab and evaluated the extent to which the use of concomitant NSAID can be reduced between weeks 4 and 12 in r-axSpA patients treated with secukinumab 150 mg compared with placebo. Methods: ASTRUM was a prospective 24-week randomized controlled trial of adult patients with active r-axSpA [Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ⩾4] who had a documented inadequate response to ⩾2 NSAIDs. Patients were randomized (1:1:1) to initiate treatment with subcutaneous secukinumab 150 mg from either week 0 (group 1), week 4 (group 2), or week 16 (group 3). From week 4 onward, tapering of NSAIDs was allowed in all groups. Results: This study included 211 patients (n = 71, 70, and 70 in groups 1, 2, and 3, respectively). ASAS20 response at week 12 for pooled groups 1 and 2 versus group 3 was 51.1% versus 44.3% (p = 0.35). A higher proportion of patients in groups 1 and 2 achieved ASAS40 and BASDAI50 and showed improvements in other secondary clinical outcomes as compared to group 3 at week 16. More patients in groups 1 and 2 versus group 3 stopped their NSAID intake from baseline through week 16. Conclusion: Treatment with secukinumab improved clinical outcomes and showed a short-term NSAID-sparing effect in patients with r-axSpA, even though the primary endpoint was not met. Trial registration: ClinicalTrials.gov; NCT02763046, EudraCT 2015-004575-74.

The CD14(bright) CD16+ monocyte subset is expanded in rheumatoid arthritis and promotes expansion of the Th17 cell population.

OBJECTIVE: Circulating monocytes contain a subpopulation of CD14+CD16+ cells; this subpopulation of cells has been described to be proinflammatory and to have an increased frequency in rheumatoid arthritis (RA). New evidence suggests that this subpopulation can be further subdivided into CD14(dim) CD16+ and CD14(bright) CD16+ cells. The aim of this study was to determine which of the two CD16+ monocyte subpopulations is expanded in patients with RA and to investigate their possible role in disease pathogenesis. METHODS: The frequencies of monocyte subpopulations in the peripheral blood of healthy donors and patients with RA were determined by flow cytometry. Monocyte subpopulations were sorted and cocultured with CD4+ T cells. Cytokines were determined in the supernatant, and Th17 cell frequencies were measured by flow cytometry. RESULTS: In comparison with the other monocyte subpopulations, CD14(bright) CD16+ cells showed higher HLA-DR and CCR5 expression and responded with higher tumor necrosis factor production to direct cell contact with preactivated T cells. They were observed at increased frequencies in the peripheral blood of patients with RA, while CD14(dim) CD16+ monocyte frequencies were not increased. CD14(bright) CD16+ cells were extremely potent inducers of Th17 cell expansion in vitro. Their frequency in the peripheral blood of patients with RA correlated closely with Th17 cell frequencies determined ex vivo. CONCLUSION: This study is the first to provide a link between the increased frequency of the CD14(bright) CD16+ monocyte subpopulation in RA and the expansion of Th17 cells, which are likely to have a role in the pathogenesis of autoimmunity.

Association of anticytomegalovirus seropositivity with more severe joint destruction and more frequent joint surgery in rheumatoid arthritis.

OBJECTIVE: Expansion of autoreactive CD4+CD28(null) T cells is associated with extraarticular disease manifestations, including rheumatoid vasculitis, and it has recently been demonstrated that expansion of these T cells is associated with anticytomegalovirus (anti-CMV) seropositivity. This study was undertaken to investigate a possible link between latent CMV infection and rheumatoid arthritis (RA). METHODS: In a retrospective analysis, anti-CMV antibodies and clinical, serologic, and radiologic parameters of joint destruction were examined in 202 RA patients and 272 healthy controls. In addition, frequencies of CD4+CD28(null) T cells; concentrations of the cytokines monocyte chemotactic protein 1 (MCP-1), interferon-α (IFNα), and IFN-inducible protein 10; and anti-CMV-specific T cell responses were analyzed in RA patients. RESULTS: Overall, no significant difference in the frequency of anti-CMV seropositivity between RA patients and healthy controls was observed. Among individuals older than age 55 years, however, anti-CMV IgG antibodies were significantly more frequent in RA patients than controls (65.3% and 54.7%, respectively; P = 0.05). Anti-CMV seropositivity in RA patients was associated with an increased frequency of CD4+CD28(null) T cells and increased serum concentrations of MCP-1. The frequency of anti-CMV-specific CD4+ T cells producing IFNγ was increased in RA patients compared to controls. Most importantly, anti-CMV-seropositive RA patients showed radiographic evidence of more advanced joint destruction and had increased frequencies of joint-related surgical procedures, indicating more severe joint disease. CONCLUSION: Our findings indicate that latent CMV infection aggravates the clinical course of RA and is associated with increased frequencies of CD4+CD28(null) T cells and of CMV-specific IFNγ-secreting CD4+ T cells.

Influenza, Pneumococcal and Herpes Zoster Vaccination Rates in Patients with Autoimmune Inflammatory Rheumatic Diseases.

BACKGROUND: Vaccination rates are known to be low in patients with autoimmune inflammatory rheumatic diseases (AIIRD). We therefore aimed to determine current vaccination rates against influenza, Streptococcus pneumoniae and herpes zoster in a cohort of patients with AIIRD in Germany. METHODS: Consecutive adult patients with an AIIRD were recruited from our outpatient clinic during their regular consultations. The individual vaccination status regarding influenza, Streptococcus pneumoniae and herpes zoster was obtained by reviewing the vaccination documents. RESULTS: A total of 222 AIIRD patients (mean age 62.9 ± 13.9 years) were included. In total, 68.5% were vaccinated against influenza, 34.7% against Streptococcus pneumoniae and 13.1% against herpes zoster (HZ). The pneumococcal vaccination was outdated in 29.4% of the vaccinated patients. Vaccination rates were significantly higher in patients ≥60 years old (odds ratio (OR) 2.167, 95% confidence interval (CI) 1.213-3.870, p = 0.008 for influenza, OR 4.639, 95% CI 2.555-8.422, p < 0.0001 for pneumococcal and OR 6.059, 95% CI 1.772-20.712, p = 0.001 for HZ vaccination). Ages > 60 years, female sex, glucocorticoid use and influenza vaccination were all independently associated with a pneumococcal vaccination. Regarding influenza vaccination, only a positive pneumococcal vaccination history remained independently associated. In patients with HZ vaccination, glucocorticoid use and a preceding pneumococcal vaccination were independently associated with HZ protection. CONCLUSIONS: The frequencies of vaccinations against influenza, Streptococcus pneumoniae and HZ have increased during recent years. While this can be partly explained by continuous efforts in patient education during the outpatient visits, the COVID-19 pandemic might also have contributed. Nevertheless, the persistently high incidence and mortality of these preventable diseases in patients with AIIRDs mandates further efforts to increase vaccination coverage, particularly in SLE patients.

Calcium-sensing receptor-mediated NLRP3 inflammasome activation in rheumatoid arthritis and autoinflammation.

The calcium-sensing receptor (CaSR) is expressed in many cell types - including immune cells and in particular circulating monocytes. Here, the receptor plays an important physiological role as a regulator of constitutive macropinocytosis. This review article provides an overview of the literature on the role of the calcium sensing receptor in the context of inflammatory processes. Special emphasis is laid upon the importance for monocytes in the context of rheumatoid arthritis. We have shown previously, that stimulation of the receptor by increased extracellular Ca2+ ([Ca2+]ex) triggers a pro-inflammatory response due to NLRP3 inflammasome assembly and interleukin (IL)-1ß release. The underlying mechanism includes macropinocytosis of calciprotein particles (CPPs), which are taken up in a [Ca2+]ex-induced, CaSR dependent manner, and leads to strong IL-1ß release. In rheumatoid arthritis (RA), this uptake and the resulting IL-1ß release is significantly increased due to increased expression of the receptor. Moreover, increased [Ca2+]ex-induced CPP uptake and IL-1ß release is associated with more active disease, while CaSR overexpression has been reported to be associated with cardiovascular complications of RA. Most importantly, however, in animal experiments with arthritic mice, increased local calcium concentrations are present, which in combination with release of fetuin-A from eroded bone could contribute to formation of CPPs. We propose, that increased [Ca2+]ex, CPPs and pro-inflammatory cytokines drive a vicious cycle of inflammation and bone destruction which in turn offers new potential therapeutic approaches.

IL-10 Induced by mTNF Crosslinking-Mediated Reverse Signaling in a Whole Blood Assay Is Predictive of Response to TNFi Therapy in Rheumatoid Arthritis.

(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring tmTNF crosslinking-induced IL-10 production to predict the response to TNF inhibitor (TNFi) therapy. (2) Methods: This prospective study included patients with active RA. Depending on the clinical judgment of the attending rheumatologist, either therapy with a TNF or JAK inhibitor was initiated. Clinical parameters and blood samples were obtained at baseline and after 8 weeks of therapy. The blood samples were collected using a newly developed whole-blood assay based on the principle of tmTNF reverse signalling. Subsequently, IL-10 was measured via enzyme-linked immunosorbent assay (ELISA) technique. (3) Results: 63 patients with RA were enrolled. In fifteen patients, TNFi therapy was initiated, while eight patients started a JAKi treatment. The cross-sectional analysis of all patients showed a positive correlation between tmTNF crosslinking-induced IL-10 and parameters of disease activity (CRP [r = 0.4091, p = 0.0009], DAS28 [r = 0.3303, p = 0.0082]) at baseline. In the TNFi treatment study, IL-10 was found to be significantly higher in EULAR responders than in non-responders (p = 0.0033). After initiation of JAKi treatment, in contrast, IL-10 induction was not linked to response. Longitudinal analysis of the TNFi-treated patients revealed IL-10 to decrease in responders (p = 0.04), but not in non-responders after 8 weeks of therapy. Of importance, the IL-10 production at baseline correlated inversely with TNFi response determined by ΔDAS28 in patients with TNFi treatment (r = -0.5299, p = 0.0422) while no such link was observed under JAKi therapy (p = 0.22). Receiver operation characteristics (ROC) analysis demonstrated a high performance of tmTNF/crosslinking-induced IL-10 in predicting a TNFi therapy response according to the EULAR criteria (AUC = 0.9286, 95% Confidence interval 0.7825-1.000, p = 0.0055). (4) Conclusions: In this pilot investigation, we demonstrated the feasibility of a whole-blood assay measuring tmTNF-induced IL-10 to predict clinical response to TNF inhibitor treatment. This approach might support rheumatologists in their decision for an individually tailored RA therapy.