Therapeutic strategies in preclinical stages of rheumatoid arthritis.

Modern therapies and treatment algorithms like treat to target have significantly improved outcomes in rheumatoid arthritis over the past decades. Moreover, the "window of opportunity" concept has led to early diagnosis and treatment with improved outcomes. Nevertheless, individuals are still impacted by progressive disease courses, which also inflict a socioeconomic burden. Therefore, novel concepts of treatment are investigated. One of those is the concept of primary prevention: treating patients at risk for developing rheumatoid arthritis for a short period of time so they do not develop the full disease. The initiation of treatment in preclinical phases of rheumatoid arthritis is expected to delay, halt or even prevent the disease onset or progression in the long term. This review summarizes the concept itself, current studies with their therapeutic algorithm and findings and provides a critical evaluation of pharmacological therapy in the preclinical stages of rheumatoid arthritis.

Prevalence and effects of Vitamin D receptor polymorphism on bone mineral density and metabolism in patients with systemic sclerosis: a preliminary study.

Patients with systemic sclerosis (SSc) have a disproportionately high prevalence of reduced bone mineral density (BMD). Polymorphisms of the vitamin D receptor (VDR) gene have been associated with osteoporosis in patients with autoimmune diseases. The aim of this study was to investigate the prevalence and possible effects of VDR polymorphism on BMD and bone metabolism in patients with SSc. In patients with SSc measurement of BMD was performed using dual-energy X-ray absorptiometry. VDR polymorphisms (FokI, BsmI) were genotyped using restriction fragment length polymorphism analysis. Markers of bone metabolism (calcium, osteocalcin, ß-crosslaps) were determined. Primary endpoint was the prevalence of VDR gene polymorphisms and the association with reduced BMD. Secondary endpoints included associations between bone metabolism and VDR gene polymorphism. 79 Caucasian patients with SSc were included. Overall, 83.5% had reduced BMD (51.9% osteopenia, 31.6% osteoporosis). The prevalence of VDR gene polymorphism (73% BsmI, 77% FokI) was comparable to studies in healthy and rheumatic populations. The homozygous presence of FokI polymorphism, but not BsmI, was significantly associated with reduced axial BMD. Fokl polymorphism was significantly associated with reduced CTX levels, although changes remained within the reference limits. VDR polymorphisms can frequently be found in patients with SSc in comparable prevalence to healthy and rheumatic populations. The homozygous presence of FokI polymorphism, but not BsmI, was significantly associated with reduced axial BMD. This could be a possible contributor for the high prevalence of reduced BMD in 83.5% of patients with SSc in this study.Trial registration. DRKS00032768, date: 05.10.2023, retrospectively registered.

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.

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.

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?

Camurati-Engelmann Disease: A Case-Based Review About an Ultrarare Bone Dysplasia.

Camurati-Engelmann disease or progressive diaphyseal dysplasia is a rare hereditary disease that results in a symmetrical hyperostosis of the long bones (cortical thickening) and/or the base of the skull. Camurati-Engelmann disease is also associated with myopathy and neurological manifestations. Clinically, Camurati-Engelmann disease typically presents with bone pain in the lower extremities, muscle weakness, and a wobbly, stilted gait. The disease is caused by mutations in the transforming growth factor-beta 1 gene. Up to date, about 300 cases have been described in the literature. In this case-based review, we present the clinical picture and genetic and radiological findings in a 20-yearold male patient we diagnosed with Camurati-Engelmann disease and our considerations in his treatment and compare the case to the literature. The diagnosis of Camurati-Engelmann disease was confirmed on patients' history, clinical and radiological findings, and genetic testing for transforming growth factor beta-1 mutation. The patient responded well to single therapy with zoledronic acid. Early diagnosis leads to improved clinical outcomes and increased quality of life in affected patients.

[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.

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.

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.

[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.

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.

Treatment of back pain in active axial spondyloarthritis with serial locoregional water-filtered infrared A radiation: A randomized controlled trial.

BACKGROUND: Axial spondyloarthritis (axSpA) is an inflammatory rheumatic disease primarily affecting the axial skeleton. OBJECTIVE: To evaluate the short-term effects of locoregional water-filtered infrared A radiation (sl-wIRAR) in the treatment of lower back pain in patients with axSpA. METHODS: Patients with active axSpA with non-steroidal anti-inflammatory drug (NSAID) therapy undergoing a 7-day multimodal rheumatologic complex treatment in an in-patient setting were eligible. Patients were randomly assigned to the intervention group (IG) receiving sl-wIRAR treatment of the back (2 treatments/day for 30 min each for 6 days) or to the control group (CG) receiving no treatment. Primary outcome was a between-group difference in pain after sl-wIRAR therapy measured on a numeric rating scale (NRS) (0 = no pain, 10 = worst pain). Secondary outcomes included an assessment of i) the onset and development of analgesic effects and an evaluation of whether sl-wIRAR ii) improved axSpA-specific well-being and iii) influenced serum cytokine levels. RESULTS: Seventy-one patients were enrolled, completed the trial and were analyzed (IG: 36 patients, CG: 35 patients). In the IG, there was a statistically significant change (p< 0.0005) in pain level [NRS] (1.6 ± 1.9 [5; 2]) from baseline (4.1 ± 2.4 [0; 8]) to trial completion (2.6 ± 2.0 [0; 7]) and a significant difference to the CG (p= 0.006). In the IG there was a significant improvement in axSpA-specific well-being (BAS-G) (p= 0.006). A physiologically relevant change in serum cytokine levels could not be observed. CONCLUSION: sl-wIRAR treatment can be useful in the treatment of patients with active axSpA as it leads to a rapid reduction of pain.