Autoantibody-Mediated Depletion of IL-1RA in Still's Disease and Potential Impact of IL-1 Targeting Therapies.

BACKGROUND: Adult-onset Still's disease (AOSD) and systemic juvenile idiopathic arthritis (sJIA) resemble a continuum of a rare, polygenic IL-1ß-driven disease of unknown etiology. OBJECTIVE: In the present study we sought to investigate a potential role of recently described autoantibodies neutralizing the interleukin-1(IL-1)-receptor antagonist (IL-1-Ra) in the pathogenesis of Still's disease. METHODS: Serum or plasma samples from Still's disease patients (AOSD, n = 23; sJIA, n = 40) and autoimmune and/or inflammatory disease controls (n = 478) were analyzed for autoantibodies against progranulin (PGRN), IL-1Ra, IL-18 binding protein (IL-18BP), and IL-36Ra, as well as circulating IL-1Ra and IL-36Ra levels by ELISA. Biochemical analyses of plasma IL-1Ra were performed by native Western blots and isoelectric focusing. Functional activity of the autoantibodies was examined by an in vitro IL-1ß-signaling reporter assay. RESULTS: Anti-IL-1-Ra IgG were identified in 7 (27%) out of 29 Still's disease patients, including 4/23 with AOSD and 3/6 with sJIA and coincided with a hyperphosphorylated isoform of endogenous IL-1Ra. Anti-IL-36Ra antibodies were found in 2 AOSD patients. No anti-PGRN or anti-IL-18BP antibodies were detected. Selective testing for anti-IL-1Ra antibodies in an independent cohort (sJIA, n = 34) identified 5 of 34 (14.7%) as seropositive. Collectively, 8/12 antibody-positive Still's disease patients were either new-onset active disease or unresponsive to IL-1 blocking drugs. Autoantibody-seropositivity associated with decreased IL-1Ra plasma/serum levels. Seropositive plasma impaired in vitro IL-1Ra bioactivity, which could be reversed by anakinra or canakinumab treatment. CONCLUSION: Autoantibodies neutralizing IL-1Ra may represent a novel patho-mechanism in a subgroup of Still's disease patients, which is sensitive to high-dose IL-1 blocking therapy.

Heat therapy in rheumatic and musculoskeletal diseases - an overview of clinical and molecular effects.

Rheumatic and musculoskeletal diseases (RMDs) usually lead to morphological and functional deficits of various extend, increased morbidity and a considerable loss of quality of life. Modern pharmacological treatment has become effective and can stop disease progression. Nonetheless, disease progression is often only slowed down. Moreover, pharmacological treatment does not improve functionality per se. Therefore, multimodal treatment of rheumatic disorders with physical therapy being a key element is of central importance for best outcomes. In recent years, research into physical medicine shifted from a sole investigation of its clinical effects to a combined investigation of clinical effects and potential changes in the molecular level (e.g., inflammatory cytokines and the cellular autoimmune system), thus offering new explanations of clinical effects of physical therapy. In this review we provide an overview of studies investigating different heat applications in RMDs, their effect on disease activity, pain and their influence on the molecular level.

Enhancing student understanding of rheumatic disease pathologies through augmented reality: findings from a multicentre trial.

OBJECTIVE: The possibility of combining real and virtual environments is driving the increased use of augmented reality (AR) in education, including medical training. The aim of this multicentre study was to evaluate the students' perspective on the AR-based Rheumality GO!® app as a new teaching concept, presenting six real anonymised patient cases with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA). METHODS: The study encompassed 347 undergraduate medical students (232 women and 115 men) from four medical universities in Germany (Jena, Bad Nauheim/Gießen, Nuremberg, Erlangen). The course was divided into a theoretical refresher lecture followed by six AR-based cases in each of the three indications presented in the Rheumality GO!® app. All participants evaluated the course after completion, assessing the benefit of the app from a student´s perspective using a questionnaire with 16 questions covering six subject areas. RESULTS: The use of the AR-based app Rheumality GO!® improved the understanding of pathologies in RA, PsA, and axSpA for 99% of the participants. For 98% of respondents, the concept of AR with real patient data has made a positive impact on the teaching environment. On the other hand, 82% were in favour of the use of virtual tools (e.g. AR) in addition to this conventional approach. CONCLUSION: The results of our survey showed that from medical students' perspective, an AR-based concept like the Rheumality GO!® app can complement rheumatology teaching in medical school as an effective and attractive tool though not replace bedside teaching.

[Lifestyle medication vitamin D. What evidence is available?] / Lifestyle-Medikament Vitamin D. Was gibt es an Evidenz?

An undersupply of 25-(OH) vitamin D3 (calcifediol) exists in many countries with moderate sunlight, long winters and only moderate fish consumption. Risk groups for vitamin D3 deficiency are older persons over 65 years, geriatric persons in nursing homes, infants and children/adolescents. Therefore, there are also many situations in Germany which justify vitamin D substitution; however, vitamin D3 is currently praised as a "magic bullet" against everything. But what do the data look like? Where can it help and where can it not help?

[Acceptance of video consultation among patients with inflammatory rheumatic diseases depends on gender and location-Results of an online survey among patients and physicians]. / Akzeptanz der Videosprechstunde unter Patienten/innen mit entzündlich rheumatischen Erkrankungen ist geschlechts- und ortsabhängig ­ Ergebnisse einer Online-Umfrage unter Patienten/innen und Ärzten/innen.

INTRODUCTION: In order to successfully integrate telemedicine into the daily routine of rheumatology, both the patient's and the physician's perspective are important. For this purpose, a detailed study by means of a web-based survey was conducted by the Working Group Young Rheumatology (AGJR) of the German Society for Rheumatology (DGRh) and the German Rheumatism League National Association. By means of subgroup analysis of the data regarding video consultation, the aim was now to find out which requirements and wishes patients and physicians have for video consultations. METHODS: The prospective survey was distributed via social media, QR code and email. Descriptive statistics and regression analysis related to video consultation were performed and correlations were shown. RESULTS: The data indicated positive attitudes toward video consultation on the part of both patients (n = 299) and rheumatologists (n = 129). A correlation between age and positive opinion of the video consultation was found among the patients (r = 0.161, p = 0.006), especially among female patients a positive approval of the video consultation was found with increasing age (r = 0.244, p < 0.001 to male patients: r = -0.190, p = 0.145). Regarding the travelling time to the treating rheumatologist, male patients found the video consultation more attractive with increasing travelling time (r = 0.229, p = 0.078). With respect to the wishes of patients and physicians, video consultation should be used primarily for follow-up or emergency appointments. Video consultation for initial appointments, on the other hand, was very rarely mentioned. CONCLUSION: During the COVID 19 pandemic, video consultation was increasingly popular among rheumatology patients as well as among rheumatologists.

Rheumatology residency in a European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases centre: opportunities and challenges.

Rheumatology is a growing medical speciality with many attractive points to young doctors. Residency is a demanding period of a physician's life, and choosing the right hospital for one's residency may not be easy. We report on our personal experience as Rheumatology residents in European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases (ERN-ReCONNET) centres.

Whole-body cryotherapy for the treatment of rheumatoid arthritis: a monocentric, single-blinded, randomised controlled trial.

OBJECTIVES: To evaluate effects of whole-body cryotherapy (WBC) in rheumatoid arthritis (RA). METHODS: Patients with active RA undergoing a 16-day multimodal rheumatologic complex treatment were randomly assigned to either WBC (6 applications in 14 days at -130°C for 3 min) or no treatment. The primary outcome was the difference between groups in pain on a numerical rating scale after intervention. Secondary outcomes assessed effects on i) disease activity, ii) functional capacity, iii) cytokine levels, and iv) use of analgesics. RESULTS: A total of 56 RA patients completed the trial (intervention group [IG]: 31 patients, control group [CG]: 25 patients). The mean change (± standard error) in pain after intervention was -2 in the IG (95% confidence interval [CI] -2.75 to -1.31, p<0.001) and -0.88 (95% CI -1.43 to -0.33, p=0.003) in the CG, with a baseline-adjusted between-group difference of -1.31 ± 0.4 (95% CI -2.1 to -0.53; p=0.002). Pain at the 12-week follow-up visit remained significantly below baseline values in the IG. Disease activity and functional capacity showed statistically and clinically meaningful improvement after intervention but were not significant at the 12-week follow up. TNF and IL-6 levels changed significantly in the IG. Eighteen of 31 (58%) patients of the IG reduced or discontinued analgesics at the 12-week follow-up. No WBC-related side effects were reported. CONCLUSIONS: WBC in RA reduces pain and disease activity significantly and in a clinically meaningful manner, resulting in a reduction of analgesics. These effects are potentially based on a change in cytokine levels.

Effects of multimodal rheumatologic complex treatment in patients with rheumatoid arthritis: a monocentric prospective study.

OBJECTIVES: To prospectively evaluate the effects of multimodal rheumatologic complex treatment (MRCT), a special concept of in-patient physical treatment (PT), in patients with rheumatoid arthritis (RA). METHODS: RA patients receiving a 16-day MRCT were eligible. MRCT was delivered to participants in 64 PT sessions of various modalities with a minimum of 1.400 Minutes of treatment. The primary outcome was the change in pain levels measured on a numeric rating scale (0-10) between baseline and discharge. Secondary outcomes were assessments of i) disease activity, ii) functional disabilities, iii) serum cytokine levels, iv) analgesic usage, v) patient global health and vi) patient's satisfaction with their therapeutic response to MRCT from baseline to discharge and over a 12-week follow-up. RESULTS: 53 RA patients completed the study and were analysed. Pain levels were reduced significantly and clinically meaningfully (mean ± standard error: -2.1 ± 0.3, p<0.001). Effects of MRCT lasted up to 12 weeks after discharge. After MRCT and during the 12-week follow-up use of analgesics was reduced compared to baseline. Regression analyses revealed no influencing factors on change in pain levels. Patient global health assessment remained improved throughout the entire follow-up period. No MRCT-related side effects were recorded. CONCLUSIONS: MRCT as a multimodal treatment concept with a strong emphasis on PT reduces pain significantly and in a clinically meaningful manner allowing for reduced analgesic usage.

Comparison of physician and artificial intelligence-based symptom checker diagnostic accuracy.

Symptom checkers are increasingly used to assess new symptoms and navigate the health care system. The aim of this study was to compare the accuracy of an artificial intelligence (AI)-based symptom checker (Ada) and physicians regarding the presence/absence of an inflammatory rheumatic disease (IRD). In this survey study, German-speaking physicians with prior rheumatology working experience were asked to determine IRD presence/absence and suggest diagnoses for 20 different real-world patient vignettes, which included only basic health and symptom-related medical history. IRD detection rate and suggested diagnoses of participants and Ada were compared to the gold standard, the final rheumatologists' diagnosis, reported on the discharge summary report. A total of 132 vignettes were completed by 33 physicians (mean rheumatology working experience 8.8 (SD 7.1) years). Ada's diagnostic accuracy (IRD) was significantly higher compared to physicians (70 vs 54%, p = 0.002) according to top diagnosis. Ada listed the correct diagnosis more often compared to physicians (54 vs 32%, p < 0.001) as top diagnosis as well as among the top 3 diagnoses (59 vs 42%, p < 0.001). Work experience was not related to suggesting the correct diagnosis or IRD status. Confined to basic health and symptom-related medical history, the diagnostic accuracy of physicians was lower compared to an AI-based symptom checker. These results highlight the potential of using symptom checkers early during the patient journey and importance of access to complete and sufficient patient information to establish a correct diagnosis.

[Multimodal rheumatological complex treatment : A current inventory]. / Multimodale rheumatologische Komplexbehandlung : Eine aktuelle Bestandsaufnahme.

Current data demonstrate for the first time the effects of multimodal rheumatological complex treatment (MRCT). As designed in 2005, MRCT successfully treats the pain and functional limitations caused by rheumatic and degenerative diseases and reduces disease activity. In addition to the presentation of the current evidence, the article provides concrete recommendations for implementation as well as assistance in the examination by the medical service.

[Pain reduction through physical medicine : Update on the evidence]. / Schmerzreduktion durch physikalische Medizin : Update zur Evidenz.

Epidemiological data from the core documentation of the regional cooperative rheumatism centers in Germany confirm that the symptom of pain is an immense problem in both active inflammatory rheumatic diseases and when in remission. By definition pain is an unpleasant sensory and emotional experience. In the context of inflammatory rheumatic diseases, nociceptive pain is triggered by inflammatory mediators or structurally mechanical distress via activation of the nociceptors. In addition, inflammation is also locally enhanced by the release of proinflammatory substances, such as substance P or calcitonin gene-related peptide (CGRP) from activated nociceptors. The phenomena of inflammation and pain are linked in a self-reinforcing mechanism, which explains why pain can be effectively controlled by inhibiting inflammation and, conversely, why inhibiting pain also has positive effects on the inflammatory response. This review focuses on publications on multimodal rheumatological complex treatment and thermotherapy, which, under evidence-based study criteria, showed a reduction in pain and a partial influencing of molecular markers with a subsequent influence on the development of pain and the inflammatory process. The results are presented in the context of current physiological knowledge on the development of pain.

[SAPHO syndrome : An overview and nosological differentiation of 35 disease cases]. / SAPHO-Syndrom : Ein Überblick und nosologische Differenzierung von 35 Krankheitsfällen.

The SAPHO syndrome is not a single entity but an inhomogeneous, nosologically heterogeneous complex of symptoms with unknown etiology and heterogeneous pathogenesis. Clinically subacute, recurrent or chronic disease processes and a common skin-bone association (skibo disease) can be found. Under the acronym SAPHO, chronically recurrent multifocal osteomyelitis (CRMO) is the most common disease that can occur in youth as well as adolescence. Spondylarthritis hyperostotica pustulo-psoriatica with the triad palmoplantar pustulosis, sternoclavicular hyperostosis and ossifying spinal manifestations is the most common SAPHO form found in adults. Abortive disease forms are the inflammatory anterior chest wall syndrome, extended sternoclavicular hyperostosis syndrome of the clavicle bone, acne CRMO and acne spondylarthritis. The SAPHO disease usually heals with a relatively favorable prognosis but there are also unfavorable courses with functional limitations. The diagnosis should be made based on clinical examination, imaging (x-ray, scintigraphy, magnetic resonance imaging) and/or histological bone biopsy analysis. Treatment should be interdisciplinary. Antibiotic treatment is obsolete. This article provides an overview of the SAPHO syndrome and a clinical-rheumatological imaging differentiation as well as classification of 35 cases at first presentation.

Adult lactose intolerance, calcium intake, bone metabolism and bone density in German-Turkish immigrants.

INTRODUCTION: Adult lactose intolerance (ALI) significantly alters calcium intake and absorption, and thus may promote osteoporosis. ALI is a recessive condition with a geographical north-south gradient characterised by decreased levels of intestinal lactase. PCR-based genotyping of lactase (LCT) gene polymorphisms is a safe and easy way to diagnose ALI and may complement diagnostic procedures to identify individuals at risk for reduced calcium intake and subsequently osteoporosis due to lactose malabsorption. Therefore, we investigated the frequency of ALI and its influence on calcium intake, markers of bone metabolism and bone mineral density (BMD) in a cohort of Turkish immigrants living in Germany. MATERIALS AND METHODS: We investigated single nucleotide polymorphisms of the LCT gene, calcium intake, markers of bone metabolism and BMD in 183 Turkish immigrants. RESULTS: ALI was diagnosed in 154 out of 183 (81%) probands. ALI was significantly associated with self-reported lactose intolerance (p < 0.001) and dislike for dairy products (p < 0.01). Osteopenia was diagnosed in 59 out of 183 (32%) and osteoporosis in 15 out of 183 (8%) probands. Probands with reduced BMD had ALI in 86%. All probands had a decreased calcium intake [mg/week]. There was no significant association between ALI, calcium intake, markers of bone metabolism or BMD. CONCLUSION: Turkish immigrants mostly have ALI and overall show a reduced calcium intake per week. However, ALI did not significantly influence calcium intake, markers of bone metabolism or BMD in this cohort. Therefore, ALI in Turkish immigrants does not seem to be a risk factor for osteoporosis.

Serial locally applied water-filtered infrared a radiation in axial spondyloarthritis - a randomized controlled trial.

INTRODUCTION: Aim of this randomized controlled trial was to evaluate the effects of serial locally applied water-filtered infrared A radiation (sl-wIRAR) in patients with axial spondyloarthritis (axSpA). METHODS: axSpA patients with active disease undergoing a 7-day multimodal rheumatologic complex treatment under non-steroidal anti-inflammatory drug (NSAID) therapy were eligible. Patients were randomly assigned in a 1:1 ratio. The intervention group (IG) received additional sl-wIRAR treatment of the back (2 treatments for 30 min per day for 6 days) to assess whether locally applied hyperthermia can i) reduce pain levels, ii) reduce disease activity and improve functionality and iii) whether an effect on tumor necrosis factor α (TNFα) levels is detectable. Additionally, it was examined whether a reduction in NSAID therapy could be achieved after trial completion. RESULTS: 71 patients completed the trial (IG: 36 patients, control group (CG) 35 patients). sl-wIRAR led to a significant pain reduction measured by a numeric rating scale (p < .0005) and in comparison, to the CG (p = .006). sl-wIRAR treatment resulted in a significant reduction in the Bath Anyklosing Spondylitis Disease Activity Index (BASDAI) (p = .004) and Bath Ankylosing Spondylitis Functional Index (p = .004) with no significant difference to the CG. TNF-α levels were significantly decreased (p = .001) only in the IG with a significant difference to the CG (p = .01). 26 (76%) of patients in the IC reduced their NSAID therapy after trial completion. CONCLUSION: sl-wIRAR treatment in axSpA leads to a rapid reduction in pain allowing NSAID dosage reduction. A reason for these desirable effects could be a change in TNFα levels.

The molecular basis for development of proinflammatory autoantibodies to progranulin.

Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody-positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin-antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCß1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the conversion of PGRN, and is strongly associated with the occurrence of neutralizing, proinflammatory PGRN-antibodies, indicating immunogenicity of this alternative secondary modification.