[The subanalysis of Rheuma-VOR demonstrates a considerable need for rheumatological care]. / Die Subanalyse von Rheuma-VOR zeigt den erheblichen Bedarf der rheumatologischen Versorgung auf.

BACKGROUND: Early diagnosis and treatment of inflammatory rheumatic diseases can prevent consequential damage such as permanently limited mobility and joint or organ damage. Simultaneously, there is an increasing deficit in medical care owing to the lack of rheumatological capacity. Rural regions are particularly affected. OBJECTIVES: The available unconfirmed diagnoses of the study Rheuma-VOR were analysed regarding another definitive inflammatory rheumatic disease. MATERIALS AND METHODS: The returned questionnaires of the rheumatologists participating in Rheuma-VOR were screened for definitive inflammatory rheumatic diseases other than the required diagnosis of rheumatoid arthritis, psoriatic arthritis or spondyloarthritis. RESULTS: Of 910 unconfirmed diagnoses, in 245 patients another definitive diagnosis could be confirmed. A total of 29.8% of the diagnoses corresponded to degenerative joint changes or chronic pain syndrome, whereas 26.1% involved different forms of inflammatory arthritis. The majority of diagnoses (40.5%) were collagenosis or vasculitis, DISCUSSION: The available data show that a rheumatological presentation was indicated for the majority of patients. Owing to the increasing deficits in medical care a prior selection of the patients is crucial to make optimal use of restricted rheumatological capacities.

Treatment strategies in MDA5-positive clinically amyopathic dermatomyositis: a single-center retrospective analysis.

Melanoma differentiation-associated protein 5 (MDA5) antibody positive amyopathic dermatomyositis (DM) is a rare inflammatory disease. So far, there is no official treatment guideline in MDA5 amyopathic dermatomyositis, but early and aggressive immunosuppressive combination treatment can induce a stable remission. We retrospectively analyzed a cohort of eight patients (male n = 5) that were diagnosed with MDA5-positive amyopathic DM. Patient data comprised demographics, CT-guided diagnosis of pulmonary involvement, pulmonary function testing including forced vital capacity (FVC) and diffusing capacity for carbon monoxide (DLCO) data on baseline and mean long-term follow-up of 51 months (24-92 months) to evaluate treatment strategies. Depending on severity of organ involvement treatments were individualized including cyclophosphamide, immunoglobulins and plasmapheresis. Simultaneously, oral treatment with tacrolimus was commenced in four of the eight patients. Most patients received remission maintenance therapy with a combination of tacrolimus, rituximab and low dose steroids. In all patients, improvement in FVC was recorded and five patients achieved an improvement in DLCO. An improvement in the CT imaging morphological findings was observed in four patients. Awareness for the entirety of all clinical and disease-related findings of amyopathic DM is crucial, and remission maintenance is often achieved with a combination of tacrolimus and rituximab.

Common Variable Immunodeficiency-Associated Cancers: The Role of Clinical Phenotypes, Immunological and Genetic Factors.

OBJECTIVE: The aim of this study was to investigate the prevalence of cancer and associating clinical, immunological, and genetic factors in a German cohort of patients with common variable immunodeficiency (CVID). METHODS: In this retrospective monocenter cohort study, we estimated the standardized incidence ratio (SIR) for different forms of cancer diagnosed in CVID patients. Furthermore, we evaluated the likely association of infectious and non-infectious CVID-related phenotypes with the diagnosis of cancer by calculation of the odds ratio. The genetic background of CVID in patients with cancer was evaluated with sequential targeted next-generation sequencing (tNGS) and whole-exome sequencing (WES). Patients' family history and WES data were evaluated for genetic predisposition to cancer. RESULTS: A total of 27/219 patients (12.3%) were diagnosed with at least one type of cancer. Most common types of cancer were gastric cancer (SIR: 16.5), non-melanoma skin cancer (NMSC) (SIR: 12.7), and non-Hodgkin lymphoma (NHL) (SIR: 12.2). Immune dysregulation manifesting as arthritis, atrophic gastritis, or interstitial lung disease (ILD) was associated with the diagnosis of cancer. Furthermore, diagnosis of NMSC associated with the diagnosis of an alternative type of cancer. Studied immunological parameters did not display any significant difference between patients with cancer and those without. tNGS and/or WES yielded a definite or likely genetic diagnosis in 11.1% of CVID patients with cancer. Based on identified variants in cancer-associated genes, the types of diagnosed cancers, and family history data, 14.3% of studied patients may have a likely genetic susceptibility to cancer, falling under a known hereditary cancer syndrome. CONCLUSIONS: Gastric cancer, NMSC, and NHL are the most frequent CVID-associated types of cancer. Manifestations of immune dysregulation, such as arthritis and ILD, were identified as risk factors of malignancy in CVID, whereas studied immunological parameters or the identification of a monogenic form of CVID appears to have a limited role in the evaluation of cancer risk in CVID.

Premature stroke and cardiovascular risk in primary Sjögren's syndrome.

Introduction: Primary Sjögren's syndrome (pSS) is associated with an increased prevalence of traditional risk factors and cardiovascular diseases (CVDs). The study aimed to identify specific risk factors for CVD in pSS patients. Methods: PSS patients with and without CVD were compared. All patients fulfilled the EULAR/ACR classification criteria. Patients with CVD presented at least one of the following manifestations: myocardial infarction, transient ischemic attacks, ischemic or hemorrhagic stroke, peripheral artery disease, coronary artery disease, and carotid plaques. Data were collected by a standardized protocol and review of medical records. Results: 61/312 (19.6%) pSS patients presented with CVD. Traditional risk factors such as hypertension, hypercholesterinemia and diabetes (p < 0.05), pSS manifestations, in particular vasculitis (p = 0.033) and Raynaud's phenomenon (p = 0.018) were associated with CVD. Among patients with ischemic events (28/312, 9%), particularly cerebrovascular disease (n = 12/28, 42.9%), correlations with increased EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) (p = 0.039) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) (p = 0.048) were observed. Age at first cerebrovascular event was 55.2 [48.9-69.6] years. Multivariate analysis confirmed hypertension [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.87-7.18, p < 0.001], hypercholesterinemia (OR 3.1, 95% CI 1.63-5.72, p < 0.001), male gender (OR 0.4, 95% CI 0.17-0.78, p = 0.009), Raynaud's phenomenon (OR 2.5, 95% CI 1.28-4.82, p = 0.007), and CNS involvement (OR 2.7, 95% CI 1.00-7.15, p = 0.048) as independent CVD predictors. Conclusion: Raynaud's phenomen as well as vasculitis and high ESSDAI have shown a significant association to CVD. PSS patients with cerebrovascular events were younger than expected. Knowledge about risk factors may help clinicians to identify pSS patients at risk for CVD. After diagnosis of pSS, patients should be screened for risk factors such as hypertension and receive appropriate therapy to prevent or at least reduce sequelae such as infarction. However, further investigations are necessary in order to achieve a reliable risk stratification for these patients.

[Care of rheumatology patients during the lockdown in early 2020 : Telemedicine, delegation, patient satisfaction and vaccination behavior]. / Versorgung von rheumatologischen Patienten während des Lockdowns im Frühjahr 2020 : Telemedizin, Delegation, Patientenzufriedenheit und Impfverhalten.

BACKGROUND: Telemedicine was implemented in outpatient care during the lockdown between March and May 2020. The aim of the study was to assess patients from a private practice and the university outpatient department with respect to patient satisfaction with telemedicine, COVID-19 worries and vaccination behavior and to compare the teleconsultation by a medical assistant for rheumatology (RFA) and a physician. METHODS: Patients with rheumatoid arthritis, psoriatric arthropathy or spondylarthritis without treatment modifications since the previous presentation were offered a telemedical replacement appointment within the framework of this study in the case of appointment cancellation by the treating center. Participants were randomized to a telemedicine appointment by a physician or an RFA (RFA university only). The patient history was carried out by telephone and standardized using a questionnaire. The disease activity was determined using the modified clinical disease activity score (CDAI) and the BASDAI. Subsequently, all patients received a pseudonymized evaluation questionnaire. RESULTS: In total 112/116 (96%) patients participated. Of these 88/112 (79%) returned the questionnaire. The RFAs conducted 19/112 (17%) of the telephone calls. The treatment was modified in 19/112 (17%) patients. Concerns about contracting COVID-19 correlated with high disease activity (p = 0.031) including the presence of painful joints (p = 0.001) and high pain levels (VAS ≥7, p = 0.009). These patients would have also cancelled their appointment themselves (p = 0.015). Patient satisfaction with the consultation was good (mean 4.3/5.0 modified FAPI) independent of the institution, the duration of the consultation and the consultation partner. Patients with a high pain intensity were the least satisfied (p = 0.036). Only 42/100 (38.2%) of the patients had been vaccinated against pneumococci and 59/100 (53.6%) against influenza. CONCLUSION: Telemedical care within the framework of a telephone consultation is well-suited for selected patients. With respect to patient satisfaction the delegation of a telemedical consultation to an RFA is possible. There is a need for improvement with respect to the vaccination behavior.

Novel aspects of regulatory T cell dysfunction as a therapeutic target in giant cell arteritis.

OBJECTIVES: Giant cell arteritis (GCA) is the most common primary vasculitis, preferentially affecting the aorta and its large-calibre branches. An imbalance between proinflammatory CD4+ T helper cell subsets and regulatory T cells (Tregs) is thought to be involved in the pathogenesis of GCA and Treg dysfunction has been associated with active disease. Our work aims to explore the aetiology of Treg dysfunction and the way it is affected by remission-inducing immunomodulatory regimens. METHODS: A total of 41 GCA patients were classified into active disease (n=14) and disease in remission (n=27). GCA patients' and healthy blood donors' (HD) Tregs were sorted and subjected to transcriptome and phenotypic analysis. RESULTS: Transcriptome analysis revealed 27 genes, which were differentially regulated between GCA-derived and HD-derived Tregs. Among those, we identified transcription factors, glycolytic enzymes and IL-2 signalling mediators. We confirmed the downregulation of forkhead box P3 (FOXP3) and interferon regulatory factor 4 (IRF4) at protein level and identified the ineffective induction of glycoprotein A repetitions predominant (GARP) and CD25 as well as the reduced T cell receptor (TCR)-induced calcium influx as correlates of Treg dysfunction in GCA. Inhibition of glycolysis in HD-derived Tregs recapitulated most identified dysfunctions of GCA Tregs, suggesting the central pathogenic role of the downregulation of the glycolytic enzymes. Separate analysis of the subgroup of tocilizumab-treated patients identified the recovery of the TCR-induced calcium influx and the Treg suppressive function to associate with disease remission. CONCLUSIONS: Our findings suggest that low glycolysis and calcium signalling account for Treg dysfunction and inflammation in GCA.

Limited antimicrobial efficacy of oral care antiseptics in microcosm biofilms and phenotypic adaptation of bacteria upon repeated exposure.

OBJECTIVES: The aims of this study were to investigate the antimicrobial efficacy of antiseptics in saliva-derived microcosm biofilms, and to examine phenotypic adaption of bacteria upon repeated exposure to sub-inhibitory antiseptic concentrations. METHODS: Saliva-derived biofilms were formed mimicking caries- or gingivitis-associated conditions, respectively. Microbial compositions were analyzed by semiconductor-based 16S rRNA sequencing. Biofilms were treated with CHX, CPC, BAC, ALX, and DQC for 1 or 10 min, and colony forming units (CFU) were evaluated. Phenotypic adaptation of six selected bacterial reference strains toward CHX, CPC, and BAC was assessed by measuring minimum inhibitory concentrations (MICs) over 10 passages of sub-inhibitory exposure. Protein expression profiles were investigated by SDS-PAGE. RESULTS: Both biofilms showed outgrowth of streptococci and Veillonella spp., while gingivitis biofilms also showed increased relative abundances of Actinomyces, Granulicatella, and Gemella spp. Antiseptic treatment for 1 min led to no relevant CFU-reductions despite for CPC. When treated for 10 min, CPC was most effective followed by BAC, ALX, CHX, and DQC. Stable adaptations with up to fourfold MIC increases were found in E. coli toward all tested antiseptics, in E. faecalis toward CHX and BAC, and in S. aureus toward CPC. Adapted E. coli strains showed different protein expression as compared with the wildtype strain. CONCLUSION: Antiseptics showed limited antimicrobial efficacy toward mature biofilms when applied for clinically relevant treatment periods. Bacteria showed phenotypic adaptation upon repeated sub-inhibitory exposure. CLINICAL RELEVANCE: Clinicians should be aware that wide-spread use of antiseptics may pose the risk of inducing resistances in oral bacteria.

Lung Involvement in Primary Sjögren's Syndrome-An Under-Diagnosed Entity.

Interstitial lung disease (ILD) represents a frequent extra-glandular manifestation of primary Sjögren's Syndrome (pSS). Limited published data regarding phenotyping and treatment exists. Advances in managing specific ILD phenotypes have not been comprehensively explored in patients with coexisting pSS. This retrospective study aimed to phenotype lung diseases occurring in a well-described pSS-ILD cohort and describe treatment course and outcomes. Between April 2018 and February 2020, all pSS patients attending our Outpatient clinic were screened for possible lung involvement. Clinical, laboratory and high-resolution computed tomography (HRCT) findings were analyzed. Patients were classified according to HRCT findings into five groups: usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), desquamative interstitial pneumonia (DIP), combined pulmonary fibrosis and emphysema (CPFE), and non-specific-ILD. Lung involvement was confirmed in 31/268 pSS patients (13%). One-third (10/31) of pSS-ILD patients were Ro/SSA antibody negative. ILD at pSS diagnosis was present in 19/31 (61%) patients. The commonest phenotype was UIP n = 13 (43%), followed by NSIP n = 9 (29%), DIP n = 2 (6 %), CPFE n = 2 (6 %), and non-specific-ILD n = 5 (16%). Forced vital capacity (FVC) and carbon monoxide diffusion capacity (DLCO) appeared lower in UIP and DIP, without reaching a significant difference. Treatment focused universally on intensified immunosuppression, with 13/31 patients (42%) receiving cyclophosphamide. No anti-fibrotic treatments were used. Median follow-up was 38.2 [12.4-119.6] months. Lung involvement in pSS is heterogeneous. Better phenotyping and tailored treatment may improve outcomes and requires further evaluation in larger prospective studies.

Ca2+ release and buffering effects of synthetic hydroxyapatite following bacterial acid challenge.

BACKGROUND: Synthetic particulate hydroxyapatite (HAP; Ca5(PO4)3(OH)) is used as ingredient in oral care products but its effects on cariogenic biofilms are not clear yet. The primary mode of action of HAP may be acting as a calcium phosphate reservoir when deposited in oral biofilms and release Ca2+ and (hydrogen) phosphate ions upon bacterial acid challenge. The aim of this in vitro study was to test this hypothesis by investigating release of Ca2+ ions and potential buffering effects from HAP upon bacterial acid challenge in planktonic cultures and biofilms of Streptococcus mutans. METHODS: Planktonic cultures of S. mutans were grown in BHI broth with 1% sucrose or with additional 5% HAP or 5% silica for up to 48 h. Separately, biofilms of S. mutans were grown in BHI for 72 h in total. After 24 h of this biofilm culture, either BHI alone or BHI with additional 0.5% HAP or 0.5% silica was added. After 48 h, BHI with 1% sucrose was added to allow bacterial acid formation. Ca2+ release was determined colorimetrically and pH measurements were performed using a pH electrode. For statistical analysis, non-parametrical procedures were applied (n ≥ 10; Mann-Whitney U test; α = 0.05). RESULTS: Relevant release of Ca2+ was only evident in planktonic cultures or biofilms with HAP but not in both other groups (p ≤ 0.001). In suspended biofilms with HAP, median pH was 4.77 after 72 h and about 0.5 pH units higher as compared to both other groups (4.28 or 4.32, respectively; p ≤ 0.001). CONCLUSIONS: Under the tested conditions, synthetic HAP releases Ca2+ ions upon bacterial acid challenge and may also show some buffering capacity but further studies are needed to investigate whether the concentrations tested here can also be reached clinically in dental biofilms.

Tuberculosis Specific Interferon-Gamma Production in a Current Refugee Cohort in Western Europe.

BACKGROUND: In 2015, a high number of refugees with largely unknown health statuses immigrated to Western Europe. To improve caretaking strategies, we assessed the prevalence of latent tuberculosis infection (LTBI) in a refugee cohort. METHODS: Interferon-Gamma release assays (IGRA, Quantiferon) were performed in n = 232 inhabitants of four German refugee centers in the summer of 2015. RESULTS: Most refugees were young, male adults. Overall, IGRA testing was positive in 17.9% (95% CI = 13.2⁻23.5%) of subjects. Positivity rates increased with age (0% <18 years versus 46.2% >50 years). Age was the only factor significantly associated with a positive IGRA in multiple regression analysis including gender, C reactive protein, hemoglobin, leukocyte, and thrombocyte count and lymphocyte, monocyte, neutrophil, basophil, and eosinophil fraction. For one year change in age, the odds are expected to be 1.06 times larger, holding all other variables constant (p = 0.015). CONCLUSION: Observed LTBI frequencies are lower than previously reported in similar refugee cohorts. However, as elderly people are at higher risk for developing active tuberculosis, the observed high rate of LTBI in senior refugees emphasizes the need for new policies on the detection and treatment regimens in this group.

Bone turnover markers failed to predict the occurrence of osteonecrosis of the femoral head: a preliminary study.

BACKGROUND: The early detection of osteonecrosis of the femoral head (ONFH) is difficult, but important for prevention of destruction of the femoral head. The objective of this study was to determine whether the occurrence of osteonecrosis of the femoral head (ONFH) correlates with changes in bone turnover markers. METHODS: In 40 patients undergoing primary total hip arthroplasty (THA), different bone turnover markers and hormones (bone specific alkaline phosphatase, osteocalcin, beta cross-laps, 25-hydroxy-cholecalciferol, and parathormone) gained from blood were determined on the morning of the surgery. Twenty-two patients needed a THA due to progressed ONFH. In 18 cases blood was gained from patients with the indication for a THA given due to advanced osteoarthritis (AO) of the hip. RESULTS: Bone specific alkaline phosphatase, osteocalcin, beta cross-laps, and parathormone did not show any deviation from standard values, neither for the group of osteonecrosis nor for the osteoarthritis group. 25-Hydroxy-cholecalciferol revealed on average decreased values without significant differences between both groups (P < 0.05). The tested bone turnover markers and hormones failed to predict the occurrence of ONFH. Thus, the focus has to be put on different parameters to find a specific parameter that possibly predicts the risk of ostenecrosis and that is suited to follow up ONFH.