Arne Schäfer

Background/Objectives: Vitamin D levels tend to be lower in patients with inflammatory rheumatic diseases (IRDs), including rheumatoid arthritis (RA), but there are minimal data on vitamin D levels in rheumatology patients with inflammatory vs. non-inflammatory diagnoses. Methods: In this retrospective, observational study, we used electronic health record data from patients presenting for their first visit at a large rheumatology clinic to assess vitamin D levels and deficiency based on diagnosis, and to evaluate the association between vitamin D and inflammatory markers (including C-reactive protein [CRP]) or autoimmune markers (including rheumatoid factor [RF], anti-citrullinated peptide antibody, and anti-nuclear antibodies). Logistic regression analysis with 13 clinical variables was used to evaluate the association between vitamin D levels and IRD diagnosis, and linear regression was used to evaluate the association between vitamin D levels and CRP or RF. Results: The patient cohort included 4979 patients; 1385 (27.8%) had an IRD. Vitamin D levels were significantly lower in the IRD vs. non-inflammatory subgroup (mean [SD] of 26.6 [13.3] vs. 27.7 [14.3]; p = 0.009), but the difference was not clinically relevant given the small effect size. Vitamin D deficiency rates (<20 ng/mL) were not significantly different between the subgroups, and vitamin D was not associated with an IRD diagnosis in logistic regression analysis. In linear regression analysis, vitamin D was not associated with CRP or RF in the full patient cohort or in the subgroup with RA (n = 539). Conclusions: We conclude that vitamin D levels do not differ substantially based on IRD versus non-inflammatory diagnosis, CRP levels, or RF levels in this clinical cohort.

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: 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 (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.

Introduction /objectives: International guidelines recommend screening for latent tuberculosis infection (LTBI) and chronic viral hepatitis infections before initiating intensified immunosuppressive therapy. We assessed the prevalence of positive screening tests for LTBI, hepatitis B virus (HBV), and hepatitis C virus (HCV) in patients screened at a large rheumatology outpatient center in Germany. Method: This retrospective cohort study used electronic health records from adult rheumatology patients. The presence of LTBI was evaluated by chest X-rays, patient medical history/self-report, and QuantiFERON®-TB Gold Plus (QFT) interferon-gamma release assays. Antibodies to HBV core antigen (anti-HBc) and HCV were used to assess HBV and HCV, respectively. Statistically significant associations were evaluated by Fisher exact tests. Results: Of 697 screened patients with a rheumatological condition (61.3% female, mean age 60.0 years), 132 (18.9%) patients were positive for LTBI (99 [14.2%]), anti-HBc (39 [5.6%]), or anti-HCV (3 [0.4%]). Nine patients had more than one positive result; different infections were not significantly associated. QFT detected the most LTBI cases (59.5%) followed by patient report/history (42.4%) and chest X-rays (17.2%). Although most patients (83.8%) were positive on only one test, associations among LTBI tests were statistically significant. Biologic disease-modifying antirheumatic drug (bDMARD) use was lower in patients with a positive LTBI screening result compared with all screened patients (73.7% vs 86.4%) and targeted synthetic DMARD (tsDMARD) use was higher (10.1% vs 5.9%). Conclusions: Almost one-fifth of rheumatology patients preparing to initiate intensified immunosuppressive therapy have positive results on screening tests for LTBI or show evidence of exposure to HBV or HCV. These findings support the need for careful screening, even in “low-prevalence” countries. Key Points• Almost 20% of rheumatology patients preparing for intensified immunosuppressive therapy were  positive on screening tests for latent tuberculosis infection (LTBI) or showed evidence of exposure to  hepatitis B virus (HBV) or hepatitis C virus (HCV).• All three LTBI assessments (chest X-ray, patient medical history/self report, and interferon-gamma  release assay) were important in determining LTBI status and seldom overlapped.• Positive results for LTBI, HBV, and HCV were not significantly associated.• Compared with all screened patients, biologic disease-modifying antirheumatic drug (DMARD) use was  lower in patients with a positive LTBI result and targeted synthetic DMARD use was higher, but this  result must be interpreted with caution.

Objective: The objective of this study was to assess the potential value of patient-reported outcomes (PROs) of depression, fibromyalgia symptoms, and pain in predicting non-inflammatory vs. inflammatory diagnoses in rheumatology patients. Methods: This retrospective, single-center study evaluated electronic health record (EHR) data from adults who were seen for their first rheumatology consultation and subsequently received a diagnosis of an inflammatory (e.g., rheumatoid arthritis or spondyloarthritis) or non-inflammatory (e.g., osteoarthritis or fibromyalgia) condition. The PROs evaluated included depressive symptoms (Patient Health Questionnaire-2 [PHQ-2]), fibromyalgia symptom severity (FM SS), and pain. Results: A total of 3669 patients were evaluated, including patients with (n = 984; 26.82%) and without (n = 2685; 73.18%) inflammatory rheumatologic disease, of whom 141 (3.8%) had fibromyalgia. The non-inflammatory subgroup reported higher FM SS scores, and the inflammatory subgroup had higher pain and inflammatory markers. Bivariate models based on PHQ-2 and FM SS had a very low specificity (0.3%) for predicting non-inflammatory conditions, resulting in the misclassification of >99% of inflammatory cases. Adding pain, inflammatory markers, and other relevant EHR variables increased specificity but still resulted in a high level of misclassification. Conclusions: The PROs evaluated in this study are not suitable for predicting non-inflammatory vs. inflammatory rheumatologic disease, even when combined with other EHR variables.

Background: This study aims to determine the rate of inflammatory rheumatic diseases (IRDs) in a cohort of initial referrals and the efficacy of prioritising appointments to the early arthritis clinic (EAC) based on symptom duration. Methods: In the present study, we used algorithm-based telephone triage to assign routine care appointments according to the time between symptom onset and request for an appointment (cut-off criterion: 6 months). This retrospective, monocentric analysis evaluated the effectiveness of our triage in identifying patients with IRDs as a function of the assigned appointment category (elective, EAC, or emergency appointment). Results: A total of 1407 patients were included in the study (34.7% male; 65.3% female). Of the 1407 patients evaluated, 361 (25.7%) presented with IRD. There were significant differences in the frequency of inflammatory diagnoses between appointment categories (p < 0.001): elective 13.8%, EAC 32.9%, and emergency 45.9%. The sample without the emergency category included a total of 1222 patients. The classification into “inflammatory” or “non-inflammatory” in this subsample was as follows: Sensitivity was 37.7%, and specificity was 92.6%. The positive predictive value (PPV) was 59.8%, and the negative predictive value (NPV) was 83.6%. Overall, 80.2% of patients were correctly assigned using the appointment category and C-reactive protein (CRP). Conclusions: The algorithm-based triage system presented here, which focuses on the time between symptom onset and request for an appointment, allows for the prioritisation of appointments in favour of patients with IRDs and thus earlier initiation of therapy.

Aims To assess the liver stiffness in patients with rheumatoid arthritis treated with methotrexate monotherapy using non-invasive, ultrasound-based elastography (acoustic radiation force impulse (ARFI) imaging) in a longitudinal approach. Methods In total, 23 MTX-naive patients were longitudinally assessed using acoustic radiation force impulse (ARFI) imaging. Baseline assessments were carried out between July 2018 and April 2019, and the follow-up evaluations took place after an average of 2.6 years. The main outcome variable was the mean shear wave velocity as measured by the ARFI method. It was calculated from 10 valid ARFI measurements for each patient. Inferential statistical analyses (within-group comparisons) were performed using t-tests for dependent samples or suitable nonparametric procedures. Results The main finding was that observed ARFI shear wave velocities did not increase during the observation period. In fact, this parameter decreased over time from 1.07 m/s (SD = 0.23) at baseline without MTX exposure to 0.97 m/s (SD = 0.16) at follow-up after a mean of 2.6 years (P = 0.013). Moreover, the magnitude of the change in shear wave velocity could not be predicted by indicators of inflammation or disease activity, BMI, age, sex or NSAR intake (corresponding regression analysis: corrected R² = 0.344; P = 0.296). Conclusions No increased risk of liver fibrosis was found in RA patients treated with MTX monotherapy during observation period.

Zusammenfassung: Hintergrund: Seit dem 1. März 2017 ist medizinisches Cannabis (MC) bundesweit verschreibungsfähig. Zur Wirksamkeit von MC bei Fibromyalgiesyndrom (FMS) existieren bisher einige qualitativ unterschiedliche Studien. Fragestellung: Ziel der Untersuchung war, die Wirksamkeit von Tetrahydrocannabinol (THC) im Verlauf einer IMST hinsichtlich des Schmerzes und mehrerer psychometrischer Variablen zu untersuchen. Material und Methoden: Für die Studie wurden im Studienzeitraum (2017–2018) alle Patienten einer Schmerzstation, die an einem FMS erkrankt waren und in einem multimodalen, interdisziplinären Setting behandelt wurden, entsprechend den Einschlusskriterien selektioniert. Die Patienten wurden getrennt nach Gruppen mit und ohne THC-Medikation bzgl. der Schmerzintensität, verschiedener psychometrischer Parameter und des Analgetikaverbrauchs während des Aufenthalts untersucht. Ergebnisse: Von den 120 in die Studie eingeschlossenen FMS-Patienten wurden 62 Patienten (51,7 %) mit THC behandelt. In den Parametern Schmerzintensität, Depressivität und Lebensqualität zeigte sich eine signifikante Besserung der Gesamtgruppe während des Aufenthalts (p < 0,001), die durch den Einsatz von THC signifikant stärker ausfiel. In fünf der sieben untersuchten Analgetikagruppen konnte bei den mit THC behandelten Patienten signifikant häufiger die Dosis reduziert bzw. das Medikament abgesetzt werden. Schlussfolgerung: Die Ergebnisse liefern Hinweise dafür, dass THC als medikamentöse Alternative in Ergänzung zu den bisher in verschiedenen Leitlinien empfohlenen Substanzen für die Therapie des FMS in Betracht gezogen werden kann.

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.

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.