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Background: High rates of vitamin D deficiency have been reported in population-based studies, including those conducted in Germany. The goal of this study was to evaluate vitamin D levels and associated factors in a clinical cohort of German patients presenting to a rheumatology clinic. Methods: We conducted a retrospective observational study of electronic health record data from patients presenting to a rheumatology clinic in southern Germany. Data included demographic characteristics and vitamin D levels as measured by the Elecsys® Vitamin D total III assay (Roche). Associations between vitamin D levels and patient characteristics were evaluated by Pearson correlation analyses, t-tests, and multiple regression analyses. We also explored seasonal changes. Results: A total of 4979 patients were included; 3230 (64.9%) were female and the mean (standard deviation [SD]) age was 53.6 (15.2) years. The mean (SD) vitamin D level was 27.4 (14.0) ng/mL (range, 3–240 ng/mL). Overall, 1540 (30.9%) had vitamin D levels in the deficient range (<20 ng/mL), 1774 (35.6%) had sufficient vitamin D (20 to 30 ng/mL), 1597 (32.1%) had optimal vitamin D levels (>30 to 70 ng/mL), and 68 (1.4%) had levels >70 ng/mL. Lower vitamin D levels were significantly associated with younger age, male sex, and higher body mass index. Mean levels were significantly lower during winter months and the percentages of patients with vitamin D deficiency were higher. Conclusions: Our data indicate that low levels of vitamin D are common in clinical cohorts, particularly in men, younger adults, overweight individuals, and during winter months. Patient education and/or supplementation may help to address this issue and potentially improve patient health.

To assess the humoral response to vaccination against SARS-CoV-2 in patients with rheumatoid arthritis treated with methotrexate (MTX). In total, 142 fully vaccinated individuals were included at 6 ± 1 weeks after their second vaccination [BioNTech/Pfizer (70.4%), AstraZeneca (20.4%), and Moderna (9.2%)]. The primary goal was to assess the humoral immune response as measured by titres of neutralising antibodies against the S1 antigen of SARS-CoV-2. In a cross-sectional, single-centre study, titres were compared between patient subgroups with (n = 80) and without (n = 62) methotrexate exposure. MTX patients showed a significantly reduced humoral response to vaccination in the oldest patient subgroup (> 70 years: P = 0.038), whereas titres of neutralising antibodies were not significantly different between MTX and non-MTX patients in patients less than 70 years of age (< 56 years: P = 0.234; 56–70 years: P = 0.446). In patients > 70 years, non-MTX patients showed a maximum immune response in 76.5% of cases, whereas this percentage was reduced to 53.7% in study participants on MTX medication (effect size d = 0.21). Older age in patients with rheumatoid arthritis in combination with methotrexate results in a significantly reduced humoral response after vaccination against SARS-CoV-2. Our data underline the importance of age regarding the humoral response and may support the temporary cessation of methotrexate, particularly in elderly patients in the context of vaccination against SARS-CoV-2.

•RA patients showed lower IgG-anti-TBEV compared to HC.•In RA, IgG-anti-TBEV are influenced by age at, time since last TBEV vaccination and disease duration.•Higher IgG-anti-TBEV responses in RA patients who had received booster vaccination.•Lower natural killer cell responses in RA patients.•Immunological benefits are suggested for timely boosters. Inactivated vaccines, such as tick-borne-encephalitis-virus-(TBEV) vaccine, have been discussed as less immunogenic in elderly and in immunocompromised patients. In this controlled cross-sectional cohort study, the antibody and cellular responses after TBEV-vaccination were investigated in 36 rheumatoid arthritis (RA) patients and 112 healthy controls (HC) by evaluating IgG-anti-TBEV concentration, neutralization and relative avidity index (RAI). Cellular reactivity was assessed by IFNgamma-producing spot-forming-units (SFU) by ELISPOT assay and flow cytometry. RA patients showed lower IgG-anti-TBEV compared to HC, which were influenced by age at and time since last TBEV vaccination and disease duration. High-responders regarding cellular immunity and avidity were less frequent in RA compared to HC. RA patients who had received booster vaccinations were more likely to demonstrate higher IgG-anti-TBEV responses compared to those who had not. In conclusion, RA patients showed a negative effect of age on anti-TBEV-IgG and immunological benefits of timely booster vaccination are suggested.

ObjectivesOnly limited data are available on the risk of liver fibrosis in patients with rheumatoid arthritis on long-term methotrexate treatment. To assess the risk of liver fibrosis in patients with rheumatoid arthritis treated with methotrexate, non-invasive, ultrasound-based elastography [acoustic radiation force impulse (ARFI) imaging] was applied.MethodsIn total, 119 patients were assessed using acoustic radiation force impulse (ARFI) imaging between July 2018 and April 2019. In a cross-sectional, single-centre study design, ARFI scores were compared between patient subgroups with (n = 65) and without (n = 54) methotrexate exposure. The main outcome variable was the mean fibrosis score as measured by the ARFI method. The mean shear wave velocity was calculated from 10 valid ARFI measurements for each patient. Inferential statistical analyses (between group) were performed using ANOVA for independent samples in the case of continuous outcome variables.ResultsSixty-five patients with and fifty-four patients without MTX exposure were assessed using the ARFI elastography method. Participating patients on MTX medication (1.113 m/s) showed ARFI scores that were comparable to those of participants without MTX exposure (1.062 m/s); P = 0.228. The mean cumulative dose in the group of MTX-exposed patients was 3602 mg.ConclusionThe mean value of the repeated determination of liver density using ARFI imaging did not differ significantly between the MTX-exposed and MTX-naive patients with RA. No increased rate of liver fibrosis was found among RA patients treated with MTX.

Considering the high plasticity of FoxP3+ regulatory T (Treg) cells and Interleukin (IL)-17-producing Th17 cells, we hypothesized that a Th17 inflammatory milieu may impair the functional properties of Treg cells in chronic inflammatory arthritides. Therefore, a cross-sectional explorative analysis was set up in patients with psoriatic arthritis (PsoA), rheumatoid arthritis, or spondyloarthritis to investigate the features of Th17 and Treg cells. T cell subpopulation counts, FOXP3 mRNA expression, CpG methylation of the FOXP3 gene, and the suppressive capacity of isolated Treg cells were determined. Ex vivo analysis of PsoA-derived peripheral blood lymphocytes showed a Th17-mediated inflammation. It was accompanied by demethylation of the FOXP3 promotor and Treg-specific demethylated region (TSDR) in Treg cells which, however, resulted neither in elevated FOXP3 mRNA expression nor in increased suppressive Treg cell capacity. To clarify this conundrum, in vitro stimulation of isolated Treg cells with Th17-inducing cytokines (IL-1β, IL-6, IL-23, TGFβ), recombinant IL-17, or the anti-IL-17A antibody secukinumab was performed, demonstrating that cell culture conditions polarizing towards Th17, but not IL-17 itself, impair the suppressive function of Treg cells, accompanied by diminished FOXP3 mRNA expression due to hypermethylation of the FOXP3 promotor and TSDR. This potential causal relationship between Th17 inflammation and impaired Treg cell function requires attention regarding the development of immunomodulatory therapies.

Background Immunosenescence is characterized by a decline in naive T cells, a reduced T cell receptor repertoire, and the accumulation of terminally-differentiated and unspecifically-activated proinflammatory cells, a process called inflammageing. Premature immunosenescence is thought to be pathogenetically relevant in rheumatoid arthritis (RA), either by posing a risk factor for its development, or by advancing the rheumatic disease as a result of excess antigenic and inflammatory stimulation. We investigated parameters of immunosenescence in RA patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) only compared to patients treated additionally or exclusively with a tumor necrosis factor inhibitor (TNFi) and age-matched healthy controls to investigate the effect of RA treatment on age-associated T cell phenotypes and functions. Results The csDMARD-only treated patients, compared to the TNFi-treated patients and healthy controls, displayed an enhanced age-dependent decline in CD31 + recent thymic emigrants (RTE) and Interleukin-7 (IL-7)-receptor α-chain (CD127)-expressing CD4 + T cells participating in IL-7-associated homeostatic proliferation, a diminished proliferation of RTE and CD127 + T cells, as well as reduced T cell receptor excision circle (TREC) counts. However, whereas the RA patients exhibited reduced proportions of unspecifically activated IFNγ- and IL-17-producing T cells, TNFi initiation induced an increase in these proinflammatory cells. Conclusions Whereas a TNFi treatment seems to counteract the non-inflammatory aspects of immunosenescence, it induces increasing proportions of terminally-differentiated, cytokine-producing effector memory T cells, requiring awareness as possibly contributing to secondary autoimmune phenomena in RA.

The prognostic significance of early diagnosis and therapeutic intervention in inflammatory rheumatic diseases has been well documented. However, a shortage of rheumatologists often impedes this approach in clinical practice. Therefore, it is of importance to identify those patients referred for diagnosis who would benefit most from a specialist's care. We applied a telephone-based triage for appointment allocation during routine care. This retrospective, monocentric analysis evaluated the efficacy of our triage to identify patients with rheumatic disease with special regard to initial appointment category (elective, early arthritis clinic (EAC), or emergency appointment). Of the 1,782 patients assessed, 718 (40.3%) presented with an inflammatory rheumatic disease, and there were significant discrepancies between the appointment categories: elective 26.2%, EAC 49.2% (P ＜ 0.001) and emergency appointment 56.6% (P ＜ 0.001). We found that 61.2% of patients were allocated to the correct diagnostic category (inflammatory or noninflammatory) solely based on the telephone-based triage and 67.1% based on the combination of triage and C-reactive protein (CRP) count.

Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014–000555–93). Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9–45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04–0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04–0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. Innovative Medicine Initiative.

ObjectiveTo prospectively analyse the risk for disease relapses in patients with rheumatoid arthritis (RA) in sustained remission, either continuing, tapering or stopping disease-modifying antirheumatic drugs (DMARDs) in a prospective randomised controlled trial.MethodsReduction of Therapy in patients with Rheumatoid arthritis in Ongoing remission is a multicentre, randomised controlled, parallel-group phase 3 trial evaluating the effects of tapering and stopping all conventional and/or biological DMARDs in patients with RA in stable remission. Patients (disease activity score 28 (DAS28)<2.6 for least 6 months) were randomised into three arms, either continuing DMARDs (arm 1), tapering DMARDs by 50% (arm 2) or stopping DMARDs after 6 months tapering (arm 3). The primary endpoint was sustained remission during 12 months.ResultsIn this interim analysis, the first 101 patients who completed the study were analysed. At baseline, all patients fulfilled DAS28 remission and 70% also American College of Rheumatology- European League Against Rheumatism Boolean remission. 82.2% of the patients received methotrexate, 40.6% biological DMARDs and 9.9% other DMARDs. Overall, 67 patients (66.3%) remained in remission for 12 months, whereas 34 patients (33.7%) relapsed. The incidence of relapses was related to study arms (p=0.007; arm 1: 15.8%; arm 2: 38.9%; arm 3: 51.9%). Multivariate logistic regression identified anticitrullinated protein antibodies (ACPA) positivity (p=0.038) and treatment reduction (in comparison to continuation) as predictors for relapse (arm 2: p=0.012; arm 3: p=0.003).ConclusionsThis randomised controlled study testing three different treatment strategies in patients with RA in sustained remission demonstrated that more than half of the patients maintain in remission after tapering or stopping conventional and biological DMARD treatment. Relapses occurred particularly in the first 6 months after treatment reduction and were associated with the presence of ACPA.Trial registration number2009-015740-42.

Objectives Recently, a number of studies have explored the possible attenuation of the immune response by disease-modifying antirheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA). Our study objective was to investigate the presumed attenuated humoral response to vaccination against SARS-CoV-2 in patients with RA treated with Janus kinase (JAK) inhibitors with or without methotrexate (MTX). The immune responses were compared with controls without RA. Method The humoral vaccination response was evaluated by determining titres of neutralising antibodies against the S1 antigen of SARS-CoV-2. One hundred and thirteen fully vaccinated individuals were included at 6 ± 1 weeks after second vaccination (BioNTech/Pfizer (69.9%), AstraZeneca (21.2%), and Moderna (8.9%)). In a cross-sectional and single-centre study design, we compared titres of neutralising antibodies between patients with ( n  = 51) and without ( n  = 62) medication with JAK inhibitors. Results Treatment with JAK inhibitors led to a significantly reduced humoral response to vaccination ( P  = 0.004). A maximum immune response was seen in 77.4% of control patients, whereas this percentage was reduced to 54.9% in study participants on medication with JAK inhibitors (effect size d  = 0.270). Further subanalyses revealed that patients on combination treatment (JAK inhibitors and MTX, 9 of 51 subjects) demonstrated an even significantly impaired immune response as compared to patients on monotherapy with JAK inhibitors ( P  = 0.028; d  = 0.267). Conclusions JAK inhibitors significantly reduce the humoral response following dual vaccination against SARS-CoV-2. The combination with MTX causes an additional, significant reduction in neutralising IgG titres. Our data suggest cessation of JAK inhibitors in patients with RA in the context of vaccination against SARS-CoV-2. Key Points • It was shown that DMARD therapy with JAK inhibitors in patients with rheumatoid arthritis leads to an attenuation of the humoral vaccination response against SARS-CoV-2. • The effect under medication with JAK inhibitors was significant compared to the control group and overall moderate. • The combination of JAK inhibitors with MTX led to an additive and significant attenuation of the humoral response.