Bessel's disease-the first report of an IgG4-related disorder.

Many aspects of IgG4-related diseases were initially described during the late 19th and early 20th century. A variety of clinical presentations caused by this common pathology have been named after the researchers who first described the disorders, such as Mikulicz, Küttner, Riedel or Ormond. However, the initial description of retroperitoneal fibrosis dates back to even 50 years earlier, when in 1846, the Prussian private practitioner Raphael Jakob Kosch described a hitherto unknown constellation of symptoms and pathological findings in a famous patient. This celebrity was the mathematician and astronomer Friedrich Wilhelm Bessel, a close friend of Alexander von Humboldt and Carl Friedrich Gauss.

Neutrophils seeking new neighbors: radiotherapy affects the cellular framework and the spatial organization in a murine breast cancer model.

Neutrophils are known to contribute in many aspects of tumor progression and metastasis. The presence of neutrophils or neutrophil-derived mediators in the tumor microenvironment has been associated with poor prognosis in several types of solid tumors. However, the effects of classical cancer treatments such as radiation therapy on neutrophils are poorly understood. Furthermore, the cellular composition and distribution of immune cells in the tumor is of increasing interest in cancer research and new imaging technologies allow to perform more complex spatial analyses within tumor tissues. Therefore, we aim to offer novel insight into intra-tumoral formation of cellular neighborhoods and communities in murine breast cancer. To address this question, we performed image mass cytometry on tumors of the TS/A breast cancer tumor model, performed spatial neighborhood analyses of the tumor microenvironment and quantified neutrophil-extracellular trap degradation products in serum of the mice. We show that irradiation with 2 × 8 Gy significantly alters the cellular composition and spatial organization in the tumor, especially regarding neutrophils and other cells of the myeloid lineage. Locally applied radiotherapy further affects neutrophils in a systemic manner by decreasing the serum neutrophil extracellular trap concentrations which correlates positively with survival. In addition, the intercellular cohesion is maintained due to radiotherapy as shown by E-Cadherin expression. Radiotherapy, therefore, might affect the epithelial-mesenchymal plasticity in tumors and thus prevent metastasis. Our findings underscore the growing importance of the spatial organization of the tumor microenvironment, particularly with respect to radiotherapy, and provide insight into potential mechanisms by which radiotherapy affects epithelial-mesenchymal plasticity and tumor metastasis.

["Rheuma (be-)greifen"- A multimodal teaching concept to improve rheumatology education for medical students]. / "Rheuma (be-)greifen" ­ ein multimodales Lehrkonzept zur Verbesserung der rheumatologischen Lehre für Studierende der Humanmedizin.

BACKGROUND: The German Society for Rheumatology, through its campaign Rheuma2025, aims to improve student teaching in order to ensure patient care for rheumatological patients in the future. OBJECTIVE: To assess whether a combination of traditional and innovative educational methods provide both an improvement in the quality of teaching and an increase in the attractiveness of rheumatology as a discipline. MATERIAL AND METHODS: Establishment of the teaching concept "Rheuma (be-)greifen" consisting of five modules on patient history taking with acting patients, musculoskeletal ultrasound, arthrocentesis, 3D printing of pathological joints and virtual reality applications based on real patient cases in the curricular teaching of medical students. RESULTS: The evaluation of the teaching concept with 93 students of medicine showed a consistently high acceptance of all modules, which were rated as very effective or rather effective. Direct patient-related modules, such as history taking with acting patients, musculoskeletal ultrasound and arthrocentesis, received even higher acceptance than the visualization methods utilizing 3D printing and virtual reality. CONCLUSION: Innovative teaching methods can help to improve the acceptance of teaching in the field of rheumatology, especially when combined with classical teaching contents.

Healthcare utilization and unmet needs of patients with antisynthetase syndrome: An international patient survey.

Antisynthease syndrome (ASSD) is a rare, complex and understudied autoimmune disease. Internet-based studies can overcome barriers of traditional on-site research and are therefore very appealing for rare diseases. The aim of this study was to investigate patient-reported symptoms, diagnostic delay, symptoms, medical care, health status, working status, disease knowledge and willingness to participate in research of ASSD patients by conducting an international web-based survey. The multilingual questionnaire was created by an international group of rheumatologists and patients and distributed online. 236 participants from 22 countries completed the survey. 184/236 (78.0%) were female, mean age (SD) was 49.6 years (11.3) and most common antisynthetase antibody was Jo-1 (169/236, 71.6%). 79/236 (33.5%) reported to work full-time. Median diagnostic delay was one year. The most common symptom at disease onset was fatigue 159/236 (67.4%), followed by myalgia 130/236 (55.1%). The complete triad of myositis, arthritis and lung involvement verified by a clinician was present in 42/236 (17.8%) at disease onset and in 88/236 (37.3%) during the disease course. 36/236 (15.3%) reported to have been diagnosed with fibromyalgia and 40/236 (16.3%) with depression. The most reported immunosuppressive treatments were oral corticosteroids 179/236 (75.9%), followed by rituximab 85/236 (36.0%). 73/236 (30.9%) had received physiotherapy treatment. 71/236 (30.1%) reported to know useful online information sources related to ASSD. 223/236 (94.5%) were willing to share health data for research purposes once a year. Our results reiterate that internet-based research is invaluable for cooperating with patients to foster knowledge in rare diseases.

Successful Generation of CD19 Chimeric Antigen Receptor T Cells from Patients with Advanced Systemic Lupus Erythematosus.

Although it has been shown that the production of functional chimeric antigen receptor T cells is feasible in patients with B-cell malignancies, it is currently unclear whether sufficient amounts of functional autologous CAR T cells can be generated from patients with autoimmune diseases. Intrinsic T-cell abnormalities and T-cell-targeted immune suppression in patients with autoimmunity may hamper the retrieval of sufficient T cells and their transduction and expansion into CAR T cells. Patients with active systemic lupus erythematosus (SLE) underwent leukapheresis after tapering glucocorticoids and stopping T-cell-suppressive drugs. This material was used as source for manufacturing anti-CD19 CAR T-cell products (CAR) in clinical scale. Cells were transduced with a lentiviral anti-CD19 CAR vector and expanded under good manufacturing practice (GMP) conditions using a closed, semi-automatic system. Functionality of these CAR T cells derived from autoimmune patient cells was tested in vitro. Six SLE patients were analyzed. Leukapheresis could be successfully performed in all patients yielding sufficient T-cell numbers for clinical scale CAR T-cell production. In addition, CAR T cells showed high expansion rates and viability, leading to CAR T cells in sufficient doses and quality for clinical use. CAR T cells from all patients showed specific cytotoxicity against CD19+ cell lines in vitro. GMP grade generation of CD19 CAR T-cell products suitable for clinical use is feasible in patients with autoimmune disease.

Prediction of response to Certolizumab-Pegol in rheumatoid arthritis (PreCePRA) by functional MRI of the brain - Study protocol for a randomized double-blind controlled study.

BACKGROUND: Tumor necrosis factor inhibitors (TNFi) signify a major advance in the treatment of rheumatoid arthritis (RA). However, treatment success initially remains uncertain as approximately half of the patients do not respond adequately to TNFi. Thus, an unmet need exists to better predict therapeutic outcome of biologicals. OBJECTIVES: We investigated whether brain activity associated with arthritis measured by functional magnetic resonance imaging (fMRI) of the brain can serve as a predictor of response to TNFi in RA patients. METHODS: PreCePRA is a multi-center, randomized, double-blind, placebo-controlled fMRI trial on patients with RA [1] [2]. Active RA patients failing csDMARDs therapy with a DAS28 > 3.2 and at least three tender and/or swollen joints underwent a brain BOLD (blood-oxygen-level dependent) fMRI scan upon joint compression at screening. Patients were then randomized into a 12-week double-blinded treatment phase with 200 mg Certolizumab Pegol (CZP) every two weeks (arm 1: fMRI BOLD signal activated volume > 2000 voxel, i.e. 2 cm3; arm 2: fMRI BOLD signal activated volume <2000 voxel) or placebo (arm 3). DAS28 low disease activity at 12 weeks was assigned as primary endpoint. A 12-week follow-up phase in which patients were switched from the placebo to the treatment arm followed the blinded phase. fMRI was carried out at screening as well as after 12 and 24 weeks of receiving CZP or placebo. CONCLUSION: We hypothesize that high-level central nervous representation of pain in patients with rheumatoid arthritis predicts response to the TNFi CZP which we further investigate in the PreCePRA trial.

gagCEST imaging at 3 T MRI in patients with articular cartilage lesions of the knee and intraoperative validation.

OBJECTIVE: The aim of this study was to compare glycosaminoglycan chemical exchange saturation transfer (gagCEST) of knee cartilage with intraoperative results for the assessment of early osteoarthritis (OA) and to define gagCEST values for the differentiation between healthy and degenerated cartilage. DESIGN: Twenty-one patients with cartilage lesions or moderate OA were examined using 3 T Magnetic Resonance Imaging (MRI). In this prospective study, regions of interest (ROIs) were examined by a sagittal gagCEST analysis and a morphological high-resolution three-dimensional, fat-saturated proton-density space sequence. Cartilage lesions were identified arthroscopically, graded by the International Cartilage Repair Society (ICRS) score in 42 defined ROIs per patient and consecutively compared with mean gagCEST values using analysis of variance and Spearman's rank correlation test. Receiver operating characteristics (ROC) curves were applied to identify gagCEST threshold values to differentiate between the ICRS grades. RESULTS: A total of 882 ROIs were examined and graduated in ICRS score 0 (67.3%), 1 (25.2%), 2 (6.2%) and the merged ICRS 3 and 4 (1.0%). gagCEST values decreased with increasing grade of cartilage damage with a negative correlation between gagCEST values and ICRS scores. A gagCEST value threshold of 3.55% was identified to differentiate between ICRS score 0 (normal) and all other grades. CONCLUSIONS: gagCEST reflects the content of glycosaminoglycan and might provide a diagnostic tool for the detection of early knee-joint cartilage damage and for the non-invasive subtle differentiation between ICRS grades by MRI even at early stages in clinical practice.

The human sialic acid-binding immunoglobulin-like lectin Siglec-9 and its murine homolog Siglec-E control osteoclast activity and bone resorption.

Regulation of osteoclast differentiation and function is a central element in bone homeostasis. While the role of soluble factors, such as cytokines, hormones and growth factors, in controlling osteoclast differentiation has been intensively characterized, the function of surface receptors is less well understood. Sialic acid-binding immunoglobulin-like lectin (Siglec)-9 and its murine homolog Siglec-E are sialic acid-recognizing inhibitory receptors from the CD33-related Siglec-family and mainly expressed on myeloid cells. We found Siglec-9 and Siglec-E to be expressed at all stages of human and murine osteoclastogenesis, respectively. Siglec-E knockout mice displayed lower bone mass despite unchanged osteoclast numbers and an increased bone formation rate. Ex vivo osteoclast assays using Siglec-E knockout cells or a blocking antibody against human Siglec-9 confirmed the suppressive effect of Siglec-9/Siglec-E on osteoclast function. Although osteoclast numbers were unchanged or even slightly decreased, the blockade/absence of Siglec-9/Siglec-E resulted in an augmented resorption activity of mature osteoclasts. This increased resorption activity was associated with enlarged actin rings. Together, our results suggest Siglec-9/Siglec-E to inhibit osteoclast activation independently from osteoclast differentiation and thereby propose a new mechanism for the control of local bone resorption.

Bone microstructure and volumetric bone mineral density in patients with hyperuricemia with and without psoriasis.

We analyzed volumetric bone mineral density (vBMD) and bone microstructure using HR-pQCT in subjects with normouricemia (NU) and subjects with hyperuricemia (HU) with and without psoriasis (PSO). HU was associated with higher cortical vBMD and thickness. Differences in average and trabecular vBMD were found between patients with PSO + HU and NU. INTRODUCTION: Hyperuricemia (HU) and gout are co-conditions of psoriasis and psoriatic arthritis. Current data suggest a positive association between HU and areal bone mineral density (BMD) and a negative influence of psoriasis on local bone, even in the absence of arthritis. However, the influence of the combination of HU and psoriasis on bone is still unclear. The aim of this study was to assess the impact of HU with and without psoriasis on bone microstructure and volumetric BMD (vBMD). METHODS: Healthy individuals with uric acid levels within the normal range (NU), with hyperuricemia (HU), patients with hyperuricemia and psoriasis (PSO + HU), and patients with uric acid within the normal range and psoriasis (PSO + NU) were included in our study. Psoriasis patients had no current or past symptoms of arthritis. Average, trabecular, and cortical vBMD (mgHA/cm3); trabecular number (Tb.N, 1/mm) and thickness (Tb.Th, mm); inhomogeneity of the network (1/N.SD, mm); and cortical thickness (Ct.Th., mm) were carried out at the ultradistal radius using high-resolution peripheral quantitative computed tomography. In addition, bone turnover markers such as DKK-1, sclerostin, and P1NP were analyzed. RESULTS: In total, 130 individuals were included (44 NU participants (34% female), 50 HU (24%), 16 PSO + HU (6%), 20 PSO + NU (60%)). Subjects were aged: NU 54.5 (42.8, 62.1), HU 57.5 (18.6, 65.1), PSO + HU 52.0 (42.3, 57.8), and PSO + NU 42.5 (34.8, 56.8), respectively. After adjusting for age, sex, BMI, and diabetes, patients in the HU group revealed significantly higher values of cortical vBMD (p < 0.001) as well as cortical thickness (p = 0.04) compared to the NU group. PSO + NU showed no differences to NU, but PSO + HU demonstrated both lower average (p = 0.03) and trabecular vBMD (p = 0.02). P1NP was associated with average, cortical, and trabecular vBMD as well as cortical thickness while sclerostin levels were related to trabecular vBMD. CONCLUSION: Hyperuricemia in otherwise healthy subjects was associated with a better cortical vBMD and higher cortical thickness. However, patients with both psoriasis and hyperuricemia revealed a lower vBMD.

[Chondrocalcinosis: idiopathic or manifestation of rare metabolic diseases?] / Chondrokalzinose: Idiopathisch oder Manifestation seltener metabolischer Erkrankungen?

Calcification in hyaline and fibrocartilage is caused by the deposition of calcium pyrophosphate dehydrate, commonly referred to as chondrocalcinosis. Clinically, this can lead to arthritis symptoms similar to a gout attack -"pseudogout". Nonetheless, also chronic or asymptomatic disease courses are possible. The prevalence of chondrocalcinosis increases with age. The diagnostic workup of degenerative joint disease, therefore, often reveals calcifications of articular cartilage as harmless incidental findings. However, particularly in patients younger than 60 years of age, chondrocalcinosis can be the symptom of an underlying metabolic disease. This review article highlights these rare diseases and presents unusual manifestations of chondrocalcinosis.

The ageing joint-standard age- and sex-related values of bone erosions and osteophytes in the hand joints of healthy individuals.

OBJECTIVE: To analyze the age-related changes of the physiological hand joint architecture. METHOD: To address this concept, healthy individuals (each 10 women and 10 men in six different age decades spanning from 21 to 80 years) were recruited through a field campaign, investigated for the absence of rheumatic diseases and other comorbidities and received high-resolution quantitative computed tomography (HR-pQCT) examination of the hand joints. Number and extent of erosions and osteophytes were quantified across the ages and different sexes. RESULTS: Bone erosions [median (Q1-Q3), 1 (0-2)] and osteophytes [2 (1-4)] were found in healthy women and men with no significant sex differences. Structural changes however accumulated with age: the overall incidence rate ratio (IRR) for the number of erosions and osteophytes per age were 1.04 (95% CI: erosions 1.03-1.06; osteophytes: 1.03-1.05). This means a 4% increase in the number of erosions and osteophytes per year. Using third decade as reference, healthy individuals in the age decades from 50 years had higher IRR for erosion numbers (sixth, seventh, eigth decade: 4.87 (2.20-11.75), 6.81 (3.08-16.46) and 6.92 (3.11-16.79)) compared to younger subjects (fourth, fifth decade: 1.80 (0.69-4.87), 1.53 (0.59-4.10)). The IRRs of osteophytes also indicate a gradual increase after the fifth decade, with IRRs of 2.32 (1.32-4.17), 4.17 (2.38-7.49) and 6.86 (3.97-12.20) for the sixth, seventh and eigth decades, respectively. CONCLUSIONS: Structural changes in the hand joints of healthy individuals are age dependent. While being rare under 50 years of age, erosions and osteophytes accumulate above the age of 50, suggesting that the threshold between "normal" and "pathological" is shifted with the increase of age.

[Erdheim-Chester disease : An important differential diagnosis and its main symptoms]. / Morbus Erdheim-Chester : Eine wichtige Differenzialdiagnose und ihre Leitsymptome.

BACKGROUND: During the last 3 years 4 patients were admitted to this hospital with a wide variety of different symptoms, in whom Erdheim-Chester disease (ECD) was diagnosed via different diagnostic pathways. OBJECTIVE: Based on four clinical cases of ECD and using additional information from the literature, this article presents the symptoms of ECD. Furthermore, similarities and differences in comparison to important rheumatological differential diagnoses are presented. RESULTS: The ECD is a multi-organ orphan disease. Typical for the disease are long bone involvement, periarterial inflammation especially of the aorta, retroperitoneal and perirenal fibrosis with so-called hairy kidneys in abdominal computed tomography (CT) scans. Treatment is increasingly directed towards the presence of a BRAF mutation, which enables targeted and effective treatment with BRAF inhibitors. CONCLUSION: The ECD is a rare differential diagnosis to rheumatic diseases that causes various and often nonspecific symptoms. Due to modern diagnostic methods with imaging procedures and biopsies it is possible to establish a precise diagnosis and provide a targeted and effective treatment.

[Research consortium Neuroimmunology and pain in the research network musculoskeletal diseases]. / Forschungsverbund Neuroimmunologie und Schmerz (Neuroimpa) im Forschungsnetz Muskuloskelettale Erkrankungen.

BACKGROUND: The research consortium Neuroimmunology and Pain (Neuroimpa) explores the importance of the relationships between the immune system and the nervous system in musculoskeletal diseases for the generation of pain and for the course of fracture healing and arthritis. MATERIAL AND METHODS: The spectrum of methods includes analyses at the single cell level, in vivo models of arthritis and fracture healing, imaging studies on brain function in animals and humans and analysis of data from patients. RESULTS: Proinflammatory cytokines significantly contribute to the generation of joint pain through neuronal cytokine receptors. Immune cells release opioid peptides which activate opioid receptors at peripheral nociceptors and thereby evoke hypoalgesia. The formation of new bone after fractures is significantly supported by the nervous system. The sympathetic nervous system promotes the development of immune-mediated arthritis. The studies show a significant analgesic potential of the neutralization of proinflammatory cytokines and of opioids which selectively inhibit peripheral neurons. Furthermore, they show that the modulation of neuronal mechanisms can beneficially influence the course of musculoskeletal diseases. DISCUSSION: Interventions in the interactions between the immune system and the nervous system hold a great therapeutic potential for the treatment of musculoskeletal diseases and pain.