Association of Serum Soluble Transferrin Receptor Concentration With Markers of Inflammation: Analysis of 1001 Patients From a Tertiary Rheumatology Center.

OBJECTIVE: Soluble transferrin receptor (sTfR) is considered to be a useful biomarker for the diagnosis of iron deficiency, especially in the setting of inflammation, as it is thought to not be affected by inflammation. We analyzed the relationship between sTfR levels and inflammatory markers in patients with known or suspected inflammatory rheumatic disease (IRD). METHODS: Blood samples of 1001 patients with known or suspected IRD referred to a tertiary rheumatology center were analyzed. Study participants were classified as patients with active IRD and patients with inactive IRD or without IRD. Correlation analyses were used to explore the relationship between sTfR levels and inflammatory markers (ie, C-reactive protein [CRP], erythrocyte sedimentation rate [ESR]). We applied multiple linear regression analysis to evaluate the predictive value of CRP levels for sTfR concentrations after adjustment for potential confounding factors. RESULTS: There were positive correlations between inflammatory markers (CRP, ESR) and serum sTfR levels (ρ 0.44, ρ 0.43, respectively; P < 0.001), exceeding the strength of correlation between inflammatory markers and the acute phase reactant ferritin (ρ 0.30, ρ 0.23, respectively; P < 0.001). Patients with active IRD demonstrated higher serum sTfR levels compared to patients with inactive or without IRD (mean 3.99 [SD 1.69] mg/L vs 3.31 [SD 1.57] mg/L; P < 0.001). After adjustment for potential confounding factors, CRP levels are predictive for serum sTfR concentrations (P < 0.001). CONCLUSION: The study provides evidence against the concept that sTfR is a biomarker not affected by inflammation.

Usefulness of Soluble Transferrin Receptor in the Diagnosis of Iron Deficiency Anemia in Rheumatoid Arthritis Patients in Clinical Practice.

Aim: We analyzed the added value of sTfR measurement in routine clinical practice to standard parameters (SP) of iron deficiency in the detection of iron deficiency anemia (IDA) in patients with rheumatoid arthritis (RA). Methods: Blood samples from 116 patients with RA were analyzed in a prospective study. Based on biochemical parameters, patients were classified as having IDA, anemia of chronic disease (ACD), IDA with concomitant ACD (ACD/IDA), or "other anemia." Sensitivity, specificity, positive (PPV), and negative predictive values (NPV) of sTfR and SP of iron status alone and in combination were calculated for the diagnosis of IDA in general, i.e., IDA or ACD/IDA. Results: In the whole sample, with regard to the diagnosis of iron deficiency (IDA or ACD/IDA), sTfR had a higher sensitivity compared both to the combined use of SP and to the combination of SP with sTfR (80.9% versus 66.7/54.8%). Specificity, PPV and NPV did not differ substantially. When patients were stratified in groups with high (CRP levels above the median, i.e., 24.1 mg/l) and low (CRP levels less or equal to the median) inflammation, the diagnostic superiority of sTfR was restricted to patients with high inflammation. In this group, the diagnostic performance of sTfR was superior both to the combined use of SP and the combination of SP with sTfR with higher sensitivity (100% versus 52.4%) and NPV (100% versus 77.7/76.7%) and comparable specificity and PPV. Conclusion: For the detection of iron depletion (IDA or ACD/IDA) in anemic RA patients, sTfR is superior to SP of iron deficiency only in highly inflammatory states.

[Hygiene measures against COVID-19 in routine outpatient care : Acceptance by the patients?] / Hygienemaßnahmen bezüglich COVID-19 in der ambulanten Versorgung : Akzeptanz durch die Patienten?

BACKGROUND: To reduce the risk of SARS-CoV­2 infections, special hygiene measures apply to all German healthcare facilities. Despite the national goals and the existence of comprehensive testing for the detection of asymptomatic or presymptomatic SARS-CoV­2 infections in all inpatients, no equivalent screening with rapid antigen tests has yet been established for outpatients. The acceptance of such screening with associated waiting times and inconvenience for affected patients has been insufficiently investigated. OBJECTIVE: We performed a self-administered anonymous survey of outpatients on their willingness to comply with the hygiene requirements, to undergo rapid antigen screening tests for asymptomatic/presymptomatic infections with SARS-CoV­2 and to receive SARS-CoV­2 vaccination. RESULTS: From 7 to 15 December 2020, 534 patients completed the survey, 195 (37%) from rheumatism and 339 (63%) from orthopedic outpatient clinics. Most patients accepted wearing a mouth-nose covering (475/534, 89%) and attending clinics without an accompanying person to prevent overcrowding of the waiting areas (450/534, 84%). A large majority (428/534 patients, 80%) accepted mandatory screening with rapid antigen tests and the associated waiting time of 15-20 min outside the hospital (449/534, 84%). More than half of the responders reported willingness to receive a SARS-CoV­2 vaccination (yes, immediately 137 (26%), yes, maybe 142 (27%) patients), with significantly (p < 0.05) more male, more rheumatic and more patients older than 60 years indicating a wish to be vaccinated. CONCLUSION: The results revealed a high acceptance of COVID-19 hygiene measures including initial screening by rapid antigen testing.

[SARS-CoV-2/COVID-19-epidemiology and prevention]. / SARS-CoV-2/COVID-19 ­ Epidemiologie und Prävention.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread globally since December 2019. A first wave is visible up to the end of June 2020 in many regions. This article presents a review of the current knowledge on the epidemiology and prevention. The SARS-CoV­2 predominantly replicates in the upper and lower respiratory tracts and is particularly transmitted by droplets and aerosols. The estimate for the basic reproduction number (R0) is between 2 and 3 and the median incubation period is 6 days (range 2-14 days). As with the related SARS-CoV and Middle East respiratory syndrome (MERS-CoV), superspreading events play an important role in the dissemination. A high proportion of infections are uncomplicated but moderate or severe courses develop in 5-10% of infected persons. Pneumonia, cardiac involvement and thromboembolisms are the most frequent manifestations leading to hospitalization. Risk factors for a complicated course are high age, hypertension, diabetes mellitus and chronic cardiovascular and pulmonary diseases as well as immunodeficiency. Currently, the estimation for the infection fatality rate (IFR) is between 0.5% and 1% across all age groups. Outbreaks were limited in many regions with bundles of various measures for reduction of social contacts. The incidence for the first wave in Germany can be estimated as 0.4-1.8% and excess mortality could not be observed.

Epidemiology of SARS-CoV-2.

PURPOSE: SARS-CoV-2 is a recently emerged ß-coronavirus. Here we present the current knowledge on its epidemiologic features. METHODS: Non-systematic review. RESULTS: SARS-CoV-2 replicates in the upper and lower respiratory tract. It is mainly transmitted by droplets and aerosols from asymptomatic and symptomatic infected subjects. The consensus estimate for the basis reproduction number (R0) is between 2 and 3, and the median incubation period is 5.7 (range 2-14) days. Similar to SARS and MERS, superspreading events have been reported, the dispersion parameter (kappa) is estimated at 0.1. Most infections are uncomplicated, and 5-10% of patients are hospitalized, mainly due to pneumonia with severe inflammation. Complications are respiratory and multiorgan failure; risk factors for complicated disease are higher age, hypertension, diabetes, chronic cardiovascular, chronic pulmonary disease and immunodeficiency. Nosocomial and infections in medical personnel have been reported. Drastic reductions of social contacts have been implemented in many countries with outbreaks of SARS-CoV-2, leading to rapid reductions. Most interventions have used bundles, but which of the measures have been more or less effective is still unknown. The current estimate for the infection's fatality rate is 0.5-1%. Using current models of age-dependent infection fatality rates, upper and lower limits for the attack rate in Germany can be estimated between 0.4 and 1.6%, lower than in most European countries. CONCLUSIONS: Despite a rapid worldwide spread, attack rates have been low in most regions, demonstrating the efficacy of control measures.

[Diagnosis, treatment and prophylaxis of herpes zoster]. / Diagnostik, Therapie und Prophylaxe des Herpes zoster.

In the case of reduced cellular immunity the previously dormant varicella zoster virus (VZV) causes the characteristic belt-shaped vesicular exanthema of herpes zoster. The initial clinical symptoms of herpes zoster are often non-specific and may lead to initial misdiagnosis. A common complication of herpes zoster is postherpetic neuralgia (PHN) but secondary hematogenic dissemination is only rarely observed. In addition to general factors, such as advanced age and female gender, inflammatory rheumatic diseases and their immunosuppressive treatment are important risk factors for the occurrence of herpes zoster. Antiviral therapy initiated in the first 72 h after the onset of exanthema reduces acute symptoms and the risk of complications. The subunit inactivated vaccine, which has been available since 2018, is highly effective and relatively well-tolerated but randomized controlled trials in patients with drug-induced immunosuppression for inflammatory rheumatic diseases are still pending.

Association between autoantibody level and disease activity in rheumatoid arthritis is dependent on baseline inflammation.

OBJECTIVES: It is still controversial whether autoantibody (AAb) serum levels have a value for response monitoring in rheumatoid arthritis (RA). Therefore, we retrospectively investigated a real-life outpatient RA cohort to determine which factors are associated with change in serum AAb levels and RA disease activity. The primary goal of the study was to determine predictors for changes in DAS28 and autoantibodies over time and identify traits of non-rituximab treated patients, which would define strong association of disease activity with changes in AAb-levels. METHODS: Seventy-eight patients with seropositive RA were monitored for DAS28, CRP, ESR, anti-cyclic citrullinated peptides (CCP), anti-mutated citrullinated vimentin (MCV), and rheumatoid factor (RF). Using linear mixed regression modelling, factors influencing DAS28 and serum AAb were determined. Patients showing above (good correlators) and below (bad correlators) average correlation of serum AAb with DAS28 were further characterised. RESULTS: In non-rituximab treated patients (88.5%), associations of changes in AAb and DAS28 were strengthened with more morning stiffness (p=0.002), DMARD use (p=0.02), tender joints (p=0.01), swollen joints (p<0.01), higher ESR (p<0.01) and VAS (p<0.001) at baseline. Decrease of anti-CCP was also predicted by longer disease duration (-4.4 U/ml per year disease duration, p=0.048) and/or no erosions (-2.0 U/ml/month, p<0.01) at baseline, whereas erosive disease predicted an increase (+1.4 U/ml/month, p=0.015) in anti-CCP. Conversely, patients with erosive disease showed a trend to decrease RF (-1.9 U/ml/month, p=0.06). CONCLUSIONS: In non-rituximab treated RA patients, the association between disease activity and change in autoantibody levels is not static, but strengthens with increase in signs of inflammation (ESR, VAS, swollen joints, tender joints, morning stiffness) at baseline. Therefore, studies of changes in AAb need to consider baseline inflammation as confounder.

[Diagnostic Work-Up for Monoarthritis - Step by Step]. / Abklärung Monarthritis ­ Schritt für Schritt.

The work-up of acute monoarthritis is challenging due to the abundance of differential diagnoses. In addition to a bacterial septic arthritis, which can, if not treated promptly, cause rapid irreversible joint damage, many diseases have to be considered: inflammatory rheumatic diseases, activated osteoarthritis, other infectious arthritis, cristal induced arthritis, and rare tumorous diseases. In cases with high urgency, and/or when medical history, physical examination and laboratory parameters remain without a specific etiologic clue, septic arthritis has to be excluded by immediate diagnostic joint aspiration. In many patients the cause of monoarthritis can already be determined by ordering a leucocyte count of the synovial fluid sample, a microscopy for crystals, and gram staining and culture for bacterial pathogens.

[Acute exacerbation of the underlying disease or infection : Which diagnostics are warranted in patients with immunosuppressive treatment for inflammatory rheumatic diseases?] / Akuter Schub der Grunderkrankung oder Infektion : Welche Diagnostik ist bei Patienten mit entzündlich rheumatischen Erkrankungen unter immunsuppressiver Therapie sinnvoll?

Infectious diseases always have to be considered in the differential diagnosis of new symptoms in patients with immunosuppressive treatment for established inflammatory rheumatic diseases. Knowledge about the specific frequency and type of infections that can be expected under immunosuppressive treatment of inflammatory rheumatic diseases as well as the diagnostic value of laboratory tests and imaging results can facilitate the often difficult differential diagnosis.

Sensitivity and Specificity of Autoantibodies Against CD74 in Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: Autoantibodies against CD74 (anti-CD74) are associated with ankylosing spondylitis (AS). The present multicenter study, the International Spondyloarthritis Autoantibody (InterSpA) trial, was undertaken to compare the sensitivity and specificity of anti-CD74 and HLA-B27 in identifying patients with nonradiographic axial spondyloarthritis (axSpA). METHODS: Patients ages 18-45 years with inflammatory back pain of ≤2 years' duration and a clinical suspicion of axSpA were recruited. HLA-B27 genotyping and magnetic resonance imaging of sacroiliac joints were performed in all patients. One hundred forty-nine patients with chronic inflammatory back pain (IBP) not caused by axSpA served as controls, and additional controls included 50 AS patients and 100 blood donors whose specimens were analyzed. RESULTS: One hundred patients with inflammatory back pain received a diagnosis of nonradiographic axSpA from the investigators and fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criteria. The mean age was 29 years, and the mean symptom duration was 12.5 months. The sensitivity of IgA anti-CD74 and IgG anti-CD74 for identifying the 100 axSpA patients was 47% and 17%, respectively. The specificity of both IgA anti-CD74 and IgG anti-CD74 was 95.3%. The sensitivity of HLA-B27 was 81%. The positive likelihood ratios were 10.0 (IgA anti-CD74), 3.6 (IgG anti-CD74), and 8.1 (HLA-B27). Assuming a 5% pretest probability of axSpA in chronic back pain patients, the posttest probability, after consideration of the respective positive test results, was 33.3% for IgA anti-CD74, 15.3% for IgG anti-CD74, and 28.8% for HLA-B27. A combination of IgA anti-CD74 and HLA-B27 results in a posttest probability of 80.2%. CONCLUSION: IgA anti-CD74 may be a useful tool for identifying axSpA. The diagnostic value of the test in daily practice requires further confirmation.

Rheumatoid Arthritis-Associated Autoimmunity Due to Aggregatibacter actinomycetemcomitans and Its Resolution With Antibiotic Therapy.

Background:Aggregatibacter actinomycetemcomitans (Aa) is a Gram-negative coccobacillus recognized as a pathogen in periodontitis and infective endocarditis. By producing a toxin (leukotoxin A, LtxA) that triggers global hypercitrullination in neutrophils, Aa has been recently linked to rheumatoid arthritis (RA) pathogenesis. Although mechanistic and clinical association studies implicate Aa infection in the initiation of autoimmunity in RA, direct evidence in humans is lacking. Case:We describe a 59-year-old man with anti-citrullinated protein antibody (ACPA)-positive RA who presented for evaluation of refractory disease. He was found to have Aa endocarditis. Following antibiotic treatment, joint symptoms resolved and ACPAs normalized. Given the implications for RA immunopathogenesis, we further investigated the bacterial, genetic and immune factors that may have contributed to the patient's clinical and autoimmune phenotypes. Methods:DNA was extracted from serum and used to amplify the Aa leukotoxin (ltx) promoter region by PCR, which was further analyzed by Sanger sequencing. High-resolution identification of HLA alleles was performed by sequenced based typing (SBT). TNF-α, IFN-γ, GM-CSF, IL-1ß, IL-6, IL-8, IL-17A, IL-18, IL-21, and IL-22 were quantified in serum by a multiplex immunoassay. IgG and IgA antibodies to Aa LtxA were assayed by ELISA. Results:Aa genotyping confirmed infection with a highly leukotoxic strain carrying a 530-bp ltx promoter deletion, shown to result in 10- to 20-fold higher bacterial expression of LtxA. Immuno-phenotyping showed high anti-LtxA antibodies, elevated cytokines implicated in RA pathogenesis (Th1/Th17), and specific host susceptibility conferred by three HLA alleles strongly linked to ACPAs and RA (DRB1*04:04, DRB1*15:01, and DPB1*04:01). One year after eradication of Aa, the patient remained free of arthritis and anti-CCP antibodies. Conclusion: In the context of genetic risk for RA, systemic subacute infection with a leukotoxic strain of Aa can drive ACPA production and a clinical phenotype similar to RA.

The ability of rheumatologists blinded to prior workup to diagnose rheumatoid arthritis only by clinical assessment: a cross-sectional study.

Objectives: We aimed to study the ability of board-certified rheumatologists, blinded to all prior diagnostic test results, to establish the presence/absence of an inflammatory rheumatic disease (IRD) or RA among polyarthralgia or arthritis patients, solely relying on clinical assessment. Methods: We performed a prospective, examiner-blinded, cross-sectional study documenting the diagnostic work in four sequential steps (medical history, physical examination, musculoskeletal ultrasonography and laboratory tests) of board-certified rheumatologists in a convenience cohort of 100 patients referred for inpatient diagnostic workup to a tertiary care rheumatology centre. Results: The ability to correctly identify patients with or without an IRD (diagnostic accuracy) increased from 27% after the clinical assessment to 53% after the ultrasonography and to 70% after taking laboratory test results into account. The corresponding values for correctly identifying patients with or without RA were 19, 42 and 60%, respectively. Therefore the diagnostic accuracy of solely clinical assessment for determining the diagnosis of IRD or RA compared with the diagnosis established by a consecutive thorough in-patient workup was only 27 and 19% in our cohort, respectively. Pretreatment with corticosteroids (in the prior 7 days) vs none did not alter these results substantially (20 vs 29% for IRD, 15% vs 20% for RA). Conclusion: Experienced rheumatologists, if deprived of information on prior external imaging and laboratory workup by blinding, were not able to correctly classify the majority of patients presenting with polyarthralgia or arthritis symptoms for inpatient workup, relying only on a brief symptom-focused medical history and physical examination.

Depression moderates the associations between beliefs about medicines and medication adherence in patients with rheumatoid arthritis: Cross-sectional study.

The 'necessity-concerns framework' postulates that patients' adherence behaviour is influenced by beliefs about the necessity and the concerns patients have regarding their prescribed medicines. We hypothesized that depression moderates the associations between beliefs about medicines and medication adherence among people with rheumatoid arthritis. Using multivariate logistic regression, we observed that people experiencing more depressive symptoms showed stronger associations between necessity beliefs and adherence as well as attenuated associations between concerns and adherence, respectively, in a cross-sectional sample ( N = 361). Thus, depression moderates the associations postulated in the 'necessity-concerns framework' in a differential way in people with rheumatoid arthritis.

High-resolution ultrasound of the midfoot: sonography is more sensitive than conventional radiography in detection of osteophytes and erosions in inflammatory and non-inflammatory joint disease.

This study aimed to compare the diagnostic value of ultrasonography to conventional radiography in detecting osteophytes and erosions in the midfoot joints in patients suffering from inflammatory and non-inflammatory joint disease. Patients with current foot radiographs were included and stratified in two cohorts: inflammatory and non-inflammatory joint disease. The ten midfoot joints of each foot were evaluated by conventional radiography assessing the presence of osteophytes and erosions and by ultrasonography determining the presence of osteophytes, erosions, and joint effusion. Power Doppler activity was scored semi-quantitatively from 0 to 3. A total of 2445 joints in 124 patients (90 with inflammatory joint disease, 34 with non-inflammatory joint disease) were assessed. Ultrasonography detected significantly more osteophytes than conventional radiography (344; 14.1% vs. 13; 0.5%), as well as more erosions (60; 2.5% vs. 3; 0.1%). There was weak agreement between the two modalities (κ-statistic 0.029-0.035). Power Doppler ultrasonography demonstrated no significant difference in hyperperfusion comparing patients with inflammatory joint disease and non-inflammatory joint disease. Ultrasonography of the midfoot is more sensitive than conventional radiography in the detection of osteophytes and erosions in patients suffering from inflammatory and non-inflammatory joint disease. Thus, midfoot ultrasonography may be a useful tool in the diagnosis of joint diseases as rheumatoid arthritis and osteoarthritis.

Pain, social support and depressive symptoms in patients with rheumatoid arthritis: testing the stress-buffering hypothesis.

This study investigated as to how social support influences health among people with rheumatoid arthritis (RA). We refer to the stress-buffering hypothesis of social support which suggests that the negative consequences of stressors on health outcomes can be buffered by social support. In this study, pain represents a stressor and depressive symptoms represent negative health outcomes. It was hypothesized that higher levels of social support should attenuate the association between pain and depression in RA. A cross-sectional study was conducted in 361 patients with RA. They completed questionnaires on social support, depression and perceived pain. Linear regression analysis was applied, with pain as the main explanatory variable, depression as a dependent variable, and an interaction term "social support × pain". Both pain and social support showed significant associations with depression, with more severe pain and lower social support going along with a higher depression score. However, the interaction term "social support × pain" was not significant, indicating that social support did not attenuate the association between pain and depression. Social support was inversely associated with the experience of depressive symptoms among people suffering from RA. However, it had no buffering effect in attenuating the postulated association between the stressor "pain" and the negative health outcomes assessed as depressive symptoms. The stress-buffering hypothesis of social support was not supported by data from this study among people suffering from RA.

Depression and inflammatory arthritis are associated in both Western and Non-Western countries: Findings from the World Health Survey 2002.

OBJECTIVES: Epidemiological studies have linked arthritis to depression. However, it remains unclear to what degree the association between arthritis and depression extends to low income countries and whether it can be replicated for inflammatory arthritis (IA). We aimed to address these knowledge gaps based on a large multi-national sample. METHODS: Cross-sectional data was drawn from the 2002 World Health Survey. IA was defined as reports of either a diagnosis or treatment of arthritis and morning stiffness for >30min. Self-reported depression was defined as positive if participants reported its prior diagnosis or treatment or if they were classified as suffering from a major depressive episode by a seven-item screening instrument. Multivariable logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CI) for the entire sample and stratified by sex and continent. RESULTS: The odds of IA was 2.6-fold increased in those with depression compared to those without (OR=2.64, 95% CI 2.18-3.21) in the entire sample. This association was observed in both men (OR=3.06, 95% CI 2.19-4.27) and women (OR=2.50, 95% CI 1.95-3.21). Similar associations were found on the continent level, but were generally stronger for the Americas and Asia compared to Africa and Europe. CONCLUSIONS: Although our definition of IA was limited by the use of self-reported morning stiffness, this study suggests that there is a positive association between inflammatory arthritis and depression in Western and Non-Western countries, suggesting that this relationship represents a universal phenomenon.

Increased extracellular water measured by bioimpedance and by increased serum levels of atrial natriuretic peptide in RA patients-signs of volume overload.

The aim of the study is to investigate water compartments in patients with rheumatoid arthritis (RA). Acute inflammatory episodes such as infection stimulate water retention, chiefly implemented by the sympathetic nervous system (SNS) and hypothalamic-pituitary-adrenal (HPA) axis. This is an important compensatory mechanism due to expected water loss (sweating etc.). Since SNS and HPA axis are activated in RA, inflammation might be accompanied by water retention. Using bioimpedance analysis, body composition was investigated in 429 controls and 156 treatment-naïve RA patients between January 2008 and December 2014. A group of 34 RA patients was tested before and after 10 days of intensified therapy. Levels of pro-atrial natriuretic peptide (proANP) and expression of atrial natriuretic peptide in synovial tissue were investigated in 15 controls and 14 RA patients. Extracellular water was higher in RA patients than controls (mean ± SEM: 49.5 ± 0.3 vs. 36.7 ± 0.1, % of total body water, p < 0.0001). Plasma levels of proANP were higher in RA than controls. RA patients expressed ANP in synovial tissue, but synovial fluid levels and synovial tissue superfusate levels were much lower than plasma levels indicating systemic origin. Systolic/diastolic blood pressure was higher in RA patients than controls. Extracellular water levels did not change in RA patients despite 10 days of intensified treatment. This study demonstrates signs of intravascular overload in RA patients. Short-term intensification of anti-inflammatory therapy induced no change of a longer-lasting imprinting of water retention indicating the requirement of additional treatment. The study can direct attention to the area of volume overload.