Axel Nigg

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.

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.

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.

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.

Objectives Only 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. Methods In 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. Results Sixty-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. Conclusion The 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.