Increased predictive value of optical spectral transmission in early rheumatoid arthritis through use of patient-adjusted cut-off scores.

OBJECTIVES: The aims of this study were to suggest patient-adjusted optical spectral transmission (OST) cut-off values for the first time and to develop clinical models that predict the probability of an early rheumatoid arthritis (RA) diagnosis based on OST findings and the 2010 American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria as a reference standard. METHODS: OST examinations were performed in newly diagnosed RA patients and healthy controls by the HandScan device. Moreover, RA patients underwent a full clinical [tender/swollen joint counts (TJC/SJC), disease activity score-28 (DAS28)] and laboratory evaluation. OST confounding factors were examined via logistic multivariate regression analyses and patient-adjusted OST-cut-offs were subsequently determined. Furthermore, statistical models to calculate the probability of an RA diagnosis, based on the measured OST values and the presence of OST influencing factors, were developed. Finally, correlations of OST with RA activity parameters were assessed. RESULTS: 1.584 joints of 72 early RA patients were examined via OST and compared to 2.200 joints of 100 healthy controls and 1.166 joints of 53 patients with non-inflammatory arthralgia (NIA), respectively. Overall OST diagnostic performance was excellent in the whole cohort between RA- and healthy control-group [Area-Under-the-Curve (AUC): 0.810 (95%CI: 0.746-0.873); p < 0.0001], and further improved in RA-patients with ≥ 1 swollen wrist/finger joint(s) [AUC: 0.841 (95%CI: 0.773-0.908); p < 0.0001]. Comparison between RA patients and patients with non-inflammatory arthralgia showed similar results by an AUC of 0.788 (95%-CI: 0.709-0.867; p < 0.0001), and further improved in RA patients with ≥ 1 swollen wrist/finger joint(s) [AUC: 0.822 (95%CI: 0.74-0.90); p < 0.0001]. For the assessment of an adjusted RA diagnosis probability, two gender-specific statistical models were developed, based on OST values and patient age. OST cut-off values of 11.2 and 18.21 were calculated for female and male patients with active disease (sensitivity 93% and 67%; specificity 71.2% and 90%), respectively. Among RA patients, OST was associated moderately/significantly with DAS28 (r = 0.42,p < 0.001) and swollen joint count (rho = 0.355,p = 0.002). CONCLUSION: The development of patient-adjusted OST cut-off values and the suggested statistical models significantly enhance OST's diagnostic performance, supporting its utility in differentiating between RA and non-inflammatory conditions. Future research should include a broader spectrum of arthritis types to validate OST's comprehensive diagnostic utility also across various inflammatory arthritides. TRIAL REGISTRATION: DRKS00016752 (German Registry of Clinical Trials).

[Effects of a multimodal inpatient treatment for patients with fibromyalgia syndrome at the Rhineland-Palatinate Acute Rheumatology Center]. / Effekte einer multimodalen stationären Behandlung bei PatientInnen mit Fibromyalgiesyndrom im Akut-Rheumazentrum Rheinland-Pfalz.

INTRODUCTION: Fibromyalgia syndrome (FMS) is a complex condition that is often refractory to therapy and is associated with impaired quality of life. In some studies, multimodal rheumatological treatment has been shown to be an effective therapy option for patients with systemic-inflammatory and degenerative rheumatic diseases. However, the effects of this therapeutic approach have not been sufficiently investigated in patients with FMS. Therefore, the aim of this study was to examine the effect of a concise 9­ to 10-day inpatient multimodal fibromyalgia treatment (MFT) using patient-reported outcomes in a German cohort. METHODS: The effects of MFT were assessed using visual analog scales (VAS) for pain (P) and subjective disease activity (DA), questionnaires measuring everyday functional capacity (Health Assessment Questionnaire [HAQ], Funktions-Fragebogen-Hannover [FFbH, Hannover Functional Ability Questionnaire]), and pharmacotherapy at three time points (Visit 1: beginning of multimodal therapy, Visit 2: end of MFT, and Visit 3: 3 months after Visit 2). RESULTS: Sixty-one patients were enrolled in the study at the Rhineland-Palatinate Acute Rheumatology Center. Under MFT, a significant improvement in VAS (P) and VAS (DA) was observed between the start and end of treatment (Visit 2 versus Visit 1: median decrease from 7 to 5, p < 0.001, for both VAS [P] and VAS [DA]). Additionally, comparison of the other two assessment points showed a change in VAS (P) (Visit 3 versus Visit 1: median decrease from 7 to 6, p = 0.041, and Visit 3 versus Visit 2: median increase from 5 to 6, p = 0.004). However, there were no significant differences in FFbH and HAQ parameters among the three visits. Examination of the subgroup of patients whose medication therapy was not intensified during hospitalization also showed significant improvements in VAS (P) and VAS (DA) between the start and end of MFB (Visit 2 versus Visit 1: median decrease from 7 to 4, p < 0.001, for VAS [P] and median decrease from 6.25 to 4, p = 0.002, for VAS [DA]). CONCLUSION: These findings indicate a demonstrable benefit to patients of MFT regarding both pain and subjective disease activity. Furthermore, pain relief was even observed 3 months after the end of therapy. This shows the high value of this therapeutic approach to treating patients with FMS.

Evolving Concepts in Treat-to-Target Strategies for Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that is characterised by a wide range of symptoms and a risk for irreversible organ damage, leading to increased morbidity and mortality. To improve long-term outcomes, innovative therapeutic goals have been explored, including attainment and maintenance of remission or low disease activity, with minimal use of glucocorticoids. Other goals encompass early diagnosis, potent yet less toxic therapies, appropriate glucocorticoid tapering, and better quality of life for the patients. Implementing a treat-to-target (T2T) approach involves treatment adjustments to achieve predefined objectives. Evidence from other chronic diseases, like hypertension and diabetes, supports the success of target-based approaches. In rheumatic diseases, the multitude of clinical features adds complexity to T2T strategies, but in rheumatoid arthritis, T2T has yielded improved outcomes. The application of T2T in SLE requires realistic therapeutic goals and practical tools for their measurement. International task forces have developed T2T recommendations for SLE, focusing on limiting disease activity, preventing organ damage, and minimising glucocorticoid use, while considering patients' quality of life. Advancements in defining clinically meaningful remission and low disease activity states, coupled with promising novel therapies, have spurred progress in the management of SLE.

[Idiopathic inflammatory myopathies : An interdisciplinary challenge]. / Idiopathische inflammatorische Myopathien : Eine interdisziplinäre Herausforderung.

Idiopathic inflammatory myopathies (IIM) are rare diseases (incidence 1:100,000) with a wide range of clinical symptoms and manifestations. Typical indicators of IIM are proximally emphasized muscle weakness and myalgias, which are usually accompanied by elevated creatine kinase levels and muscle atrophy. The autoantibody diagnostics separate IIM into different entities, which are each associated with a typical risk of organ manifestations and the occurrence of tumors. The IIM represents an interdisciplinary challenge and the diagnostics and treatment require the involvement of several disciplines including rheumatology, neurology, neuropathology, dermatology and pneumology. An accurate diagnosis and careful tumor screening are essential because of the association between certain subgroups of IIM and the occurrence of malignant tumors.

Performance of a novel high-resolution infrared thermography marker in detecting and assessing joint inflammation: a comparison with joint ultrasound.

OBJECTIVES: To examine the value of a novel high-resolution thermographic marker in the detection of joint inflammation compared to joint ultrasound (US) and to suggest thermographic cut-off values of joint inflammatory activity. METHODS: Infrared thermographies were performed in patients with inflammatory arthritides and healthy controls. Patients were moreover examined clinically and by joint-US [Power-Doppler-(PDUS), Greyscale-US (GSUS)]. Regions of interest (ROIs) were defined for every joint and absolute temperature values within the ROIs were documented. The hottest areas ("hotspots") were identified by a clustering algorithm and the Hotspot/ROI-Ratio (HRR)-values were calculated. Subsequently, the HRR of patient-joints with different grades of hypervascularity (PDUS I°-III°) were compared among each other and with PDUS 0° control-joints. Diagnostic HRR-performance was tested by receiver-operating-characteristics. RESULTS: 360 joints of 75 arthritis-patients and 1,808 joints of 70 controls were thermographically examined. HRR-values were statistically different between PDUS I-III vs. PDUS 0 and vs. healthy subjects for all four joint groups as well as in the majority of cases between patient-joints with different grades of hypervascularity (PDUS I°-III°; p<0.05). Taking joint-US as a reference, the best performance of HRR was found at the level of the wrist-joints by an area under the curve (AUC) of 0.91 (95%CI 0.84-0.98) with a sensitivity of 0.83 and specificity of 0.88. CONCLUSIONS: HRR showed an excellent performance in the differentiation of joints with US inflammatory activity from non-inflamed joints. Moreover, HRR was able to differentiate between joints with different grades of hypervascularity, making HRR a promising tool to assist disease activity monitoring.

Cardiovascular Risk Evaluation in Psoriatic Arthritis by Aortic Stiffness and the Systemic Coronary Risk Evaluation (SCORE): Results of the Prospective PSOCARD Cohort Study.

INTRODUCTION: Psoriatic arthritis (PsA) is associated with increased cardiovascular (CV) risk and mortality. Aortic stiffness measured by carotid-femoral pulse wave velocity (cfPWV) has been shown to predict CV risk in the general population. The present study aimed to examine cfPWV values of patients with PsA compared to healthy controls and to evaluate associations of cfPWV with patient- and disease-associated characteristics, as well as with an established traditional CV prediction score of the European Society of Cardiology (Systemic Coronary Risk Evaluation; SCORE), for the first time. METHODS: cfPWV and SCORE were evaluated in patients with PsA and healthy controls, along with clinical and laboratory disease parameters. Differences in cfPWV measurements between the two groups and associations of cfPWV with patient- and disease-associated characteristics were statistically evaluated. RESULTS: A total of 150 patients with PsA (PSOCARD cohort) and 88 control subjects were recruited. cfPWV was significantly higher in the PsA group compared to controls, even after adjustment for confounders (padj = 0.034). Moreover, cfPWV was independently associated with disease duration (r = 0.304, p = 0.001), age (rho = 0.688, p < 0.001), systolic arterial pressure (rho = 0.351, p < 0.001), glomerular filtration rate (inverse: rho = - 0.264, p = 0.001), and red cell distribution width, a marker of major adverse CV events (MACE) (rho = 0.190, p = 0.02). SCORE revealed an elevated CV risk in 8.73% of the patients, whereas cfPWV showed increased aortic stiffness and end-organ disease in 16.00% of the same cohort. CONCLUSIONS: In the largest cfPWV/PsA cohort examined to date, patients with PsA exhibited increased aortic stiffness compared to healthy controls. PsA duration was the most important independent disease-associated predictor of increased aortic stiffness, next to traditional CV risk factors. cfPWV measurements may help identify subclinical end-organ disease and abnormal aortic stiffness and thus assist CV risk classification in PsA.

[Current patient care of systematic lupus erythematosus in Rhineland-Palatinate and Saarland]. / Versorgungssituation des Systemischen Lupus Erythematodes in Rheinland-Pfalz und dem Saarland.

BACKGROUND: Systemic lupus erythematosus (SLE) is a clinically heterogeneous autoimmune disease that is associated with great suffering for those affected, as well as high socioeconomic costs. Early diagnosis and adequate medical care are essential for a mild course of the disease. However, there is a lack of current figures and data on the care situation of patients in the area. METHODOLOGY: A total of 1546 general practitioners, rheumatologists, neurologists, nephrologists and dermatologists in Rhineland-Palatinate and Saarland were interviewed by fax or mail using a questionnaire regarding epidemiology, symptoms, therapy and therapy success. In addition, there was the possibility of making suggestions for improvement. RESULTS: Five out of six of the 635 reported SLE patients were female. The most common main symptoms were arthralgia, fatigue, myalgia, and skin changes. Of the patients, 68% received antimalarials (AMs), whereas 46% were treated with glucocorticoids (GCs) and 50% with an immunosuppressant (IS), mainly methotrexate. In terms of comorbidities, patients suffered mainly from cardiovascular disease, fibromyalgia syndrome and depression. Rheumatologists also frequently described anaemia, diabetes mellitus and osteoporosis. DISCUSSION: Compared with guideline recommendations, the low rate of AMs in therapy was particularly striking in patients not treated by rheumatologists (35% on average compared with 81% for rheumatologists). Additionally, (sustained) high doses of GCs are not in line with literature recommendations. In the free text field, the main requests were for more rheumatologists in private practice and faster appointment scheduling, as well as better communication and networking. In addition, the desire for more training and education was frequently expressed..

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Rheuma-VOR study: optimising healthcare of rheumatic diseases by multiprofessional coordinating centres.

OBJECTIVES: Early diagnosis of inflammatory arthritis is critical to prevent joint damage and functional incapacities. However, the discrepancy between recommendations of early diagnosis and reality is remarkable. The Rheuma-VOR study aimed to improve the time to diagnosis of patients with early arthritis by coordinating cooperation between primary care physicians, specialists and patients in Germany. METHODS: This prospective non-randomised multicentre study involved 2340 primary care physicians, 72 rheumatologists, 4 university hospitals and 4 rheumatology centres in 4 German Federal States. The two coprimary endpoints (time to diagnosis and screening performance of primary care physicians) were evaluated for early versus late implementation phase. Additionally, time to diagnosis and secondary endpoints (decrease of disease activity, increase in quality of life and overall well-being, improvement of fatigue, depression, functional ability, and work ability, reduction in drug and medical costs and hospitalisation) were compared with a reference cohort of the German Rheumatism Research Centre (DRFZ) reflecting standard care. RESULTS: A total of 7049 patients were enrolled in the coordination centres and 1537 patients were diagnosed with a rheumatic disease and consented to further participation. A follow-up consultation after 1 year was realised in 592 patients. The time to diagnosis endpoint and the secondary endpoints were met. In addition, the calculation of cost-effectiveness shows that Rheuma-VOR has a dominant cost-benefit ratio compared with standard care. DISCUSSION: Rheuma-VOR has shown an improvement in rheumatological care, patient-reported outcome parameters and cost savings by coordinating the cooperation of primary care physicians, rheumatologists and patients, in a nationwide approach.

Arterial Stiffness as a Surrogate Marker of Cardiovascular Disease and Atherosclerosis in Patients with Vasculitides: A Literature Review.

Vasculitis, a group of systemic inflammatory diseases that affect the cardiovascular (CV) system, presents with a variety of clinical manifestations that depend on the size of the affected blood vessels. While some types of vasculitis reveal distinct symptoms, others are characterized by more diffuse and nonspecific presentations that can result in delayed diagnosis and treatment initiation. Interestingly, patients with vasculitides share a significant comorbidity: an elevated CV risk, contributing to increased rates of CV events and mortality. This heightened risk is caused by cumulative inflammatory burden, traditional CV risk factors, medication effects, and reduced physical fitness. Traditional risk assessment tools, commonly used in the general population, frequently underestimate the CV risk in patients with inflammatory rheumatic conditions. Consequently, novel approaches are necessary to stratify the precise CV risk in vasculitis patients. A number of surrogate parameters for CV risk have been investigated, with arterial stiffness emerging as a promising marker. Pulse wave velocity (PWV) is a well-established method for assessing arterial stiffness and predicting CV risk across different populations. Among numerous PWV variants, carotid-femoral PWV (cfPWV) stands out as the most extensively studied and accepted reference standard. It has demonstrated its utility as a surrogate CV parameter both in the general population and in patients with systemic inflammatory rheumatic diseases. In recent years, research has expanded to assess arterial stiffness in systemic rheumatic diseases, such as arthritis, connective tissue diseases, rheumatologic overlap syndromes, and chronic pain disorders, using measurements of PWV and other markers of arterial compliance and elasticity. Despite burgeoning research in rheumatologic diseases, data on CV risk markers in vasculitides remain limited and fragmented. This narrative review aims to provide a comprehensive overview of arterial stiffness as a potential screening marker for CV diseases, atheromatosis, and ultimately CV risk among patients with vasculitides.

Diagnostic Value of Labial Minor Salivary Gland Biopsy: Histological Findings of a Large Sicca Cohort and Clinical Associations.

(1) Background: The aim of this study was to analyze labial minor salivary gland biopsy (MSGB) findings of a large sicca cohort and to examine their associations with Sjogren's syndrome (SS)-associated laboratory markers, phenotypic characteristics and systemic manifestations. Moreover, we sought to explore the ability of MSGB to identify SS patients among subjects with pre-diagnosed fibromyalgia (FM). (2) Methods: Included were all patients of three rheumatology departments having undergone a diagnostic MSGB within 9 years. Next to the examination of histological and immunohistochemical findings, we focused on activity and chronicity parameters of the underlying disease, autoantibodies, presence of systemic and hematologic involvement, as well as chronic pain and SS comorbidities. (3) Results: Among the 678 included patients, 306 (45.1%) had a positive focus score (FS). The remaining patients (n = 372) served as control subjects. There were significant correlations between FS and hypergammaglobulinemia (p < 0.001), ANA and rheumatoid factor positivity (both; p < 0.001), a weak significant correlation with erythrocyte sedimentation rate (rho = 0.235; p < 0.001) and a negative correlation with nicotine use (p = 0.002). Within the primary SS subgroup, FS was associated significantly with glandular enlargement (p = 0.007) and systemic hematologic manifestations (p = 0.002). Next to FS, CD20 cell staining showed an excellent diagnostic performance in the diagnosis of SS by an area under the curve of 0.822 (95%CI 0.780-0.864; p < 0.001). Interestingly, 42.1% of all patients with fibromyalgia (FM) having received an MSGB could be diagnosed with SS. (4) Conclusion: By examining one of the largest cohorts in the literature, we could show that MSGB histological and immunohistochemical findings not only play a key role in the classification and diagnosis of SS but could also provide important information regarding SS phenotype and systemic manifestations. Furthermore, MSGB may help differentiate patients with FM from patients with subclinical SS who suffer primarily from chronic pain.

Arterial Stiffness as a Surrogate Marker of Cardiovascular Disease and Atherosclerosis in Patients with Arthritides and Connective Tissue Diseases: A Literature Review.

The increased cardiovascular (CV) risk among patients with autoimmune rheumatic diseases, such as arthritides and connective tissue diseases, has been extensively documented. From a pathophysiological standpoint, systemic inflammation in the context of the disease can lead to endothelial dysfunction, accelerated atherosclerosis, and structural changes in vessel walls, which, in turn, are associated with exaggerated CV morbidity and mortality. In addition to these abnormalities, the increased prevalence of traditional CV risk factors, such as obesity, dyslipidemia, arterial hypertension, and impaired glucose metabolism, can further worsen the status of and overall prognosis for CV in rheumatic patients. However, data on appropriate CV screening methods for patients with systemic autoimmune diseases are scarce, and traditional algorithms may lead to an underestimation of the true CV risk. The reason for this is that these calculations were developed for the general population and thus do not take into account the effect of the inflammatory burden, as well as other chronic-disease-associated CV risk factors. In recent years, different research groups, including ours, have examined the value of different CV surrogate markers, including carotid sonography, carotid-femoral pulse wave velocity, and flow-mediated arterial dilation, in the assessment of CV risk in healthy and rheumatic populations. In particular, arterial stiffness has been thoroughly examined in a number of studies, showing high diagnostic and predictive value for the occurrence of CV events. To this end, the present narrative review showcases a series of studies examining aortic and peripheral arterial stiffness as surrogates of all-cause CV disease and atherosclerosis in patients with rheumatoid and psoriatic arthritis, as well as in systemic lupus erythematosus and systemic sclerosis. Moreover, we discuss the associations of arterial stiffness with clinical, laboratory, and disease-specific parameters.

Optical spectral transmission to assess glucocorticoid therapy response in patients with arthritis: a longitudinal follow-up comparison with joint ultrasound.

BACKGROUND: Optical spectral transmission (OST) is a modern diagnostic modality, able to assess the blood-specific absorption of light transmitted through a tissue, promising quantification of inflammation in the finger and wrist joints of patients with arthritis. To date, there are no adequate data regarding the diagnostic value of OST in the evaluation of inflammatory activity changes, during arthritis follow-up. Objectives of this study were therefore to examine the performance of OST in assessing response to anti-inflammatory therapy in patients with active arthritis and to explore OST associations with clinical, laboratory, and ultrasonographic (US) activity markers. METHODS: 1173 joints of 54 patients with arthritides of the wrist and finger joints were examined by OST before and after oral administration of glucocorticoids (GC), during a disease flare. For the same time-points patients underwent clinical, laboratory, and joint US [grayscale (GSUS), power-Doppler (PDUS)] examinations. The distribution of ΔOST-values between the two time-points was compared with the respective distributions of ΔPDUS and ΔGSUS by Bayesian statistical analyses. Moreover, the diagnostic performance of OST compared to a control group (2508 joints of 114 subjects) was examined by receiver operating characteristics and associations of OST values with clinical, laboratory, and arthrosonographic parameters were evaluated by correlation analyses. RESULTS: OST and US performed similarly in the assessment of inflammatory changes caused by GC (same value-change tendency in 83.2% of the cases). Bayesian statistics revealed no significant differences between ΔOST and ΔPDUS for all 3 examined joint categories (accuracy: metacarpophalangeal (MCP): 68.1%; proximal interphalangeal (PIP): 60.4%; wrists: 50.4%) and between ΔOST and ΔGSUS for MCP and PIP joints (accuracy: 51.1% and 78.7%, respectively). OST diagnostic performance (patients vs. controls) was excellent in both time-points [area under the curve (AUC) before GC=0.883(95%CI=0.83-0.94) and after GC=0.811(95%CI=0.74-0.881); p<0.001]. Furthermore, OST correlated significantly with all examined sonographic activity scores (all; p<0.001) and with swollen joint counts (p<0.01). CONCLUSIONS: OST was able to assess response to therapy in a similar way to joint US and correlated significantly with arthritis activity markers. Therefore, OST has proved to be a valuable tool to assist disease activity monitoring in the examined cohort. TRIAL REGISTRATION: German Registry of Clinical Trials, DRKS00016752.

NMDA Receptors in Health and Diseases: New Roles and Signaling Pathways-Anti-N-Methyl-D-Aspartate Receptor (NMDAR) Autoantibodies as Potential Biomarkers of Fatigue in Patients with Rheumatic Diseases.

Fatigue is a widespread and complex symptom with motor and cognitive components; it is diagnosed predominantly by questionnaire. We recently published a correlation between anti-N-methyl-D-aspartate receptor (NMDAR) antibodies and fatigue in patients with SLE (systemic lupus erythematosus). In the present study, we examined whether this association also applies to patients with other rheumatic diseases. Serum samples of 88 patients with different rheumatic diseases were analyzed for the presence of anti-NR2 antibodies and Neurofilament light chain (NfL) protein. The severity of fatigue was determined according to the FSMC questionnaire (Fatigue Scale for Motor and Cognitive Functions) and correlated with the circulating antibody titer and NfL level accordingly. Positive titers of anti-NR2 antibodies were detected in patients with both autoimmune and non-autoimmune rheumatic diseases. These patients suffer predominantly from severe fatigue. The circulating NfL level did not correlate with the anti-NR2 titer and the fatigue severity in all patient groups. The association of severe fatigue with circulating anti-NR2 antibodies in patients with rheumatic diseases, independently from the main disease, suggests an individual role of these autoantibodies in fatigue pathophysiology. Thus, the detection of these autoantibodies might be a helpful diagnostic tool in rheumatic patients with fatigue.

Novel Surrogate Markers of Cardiovascular Risk in the Setting of Autoimmune Rheumatic Diseases: Current Data and Implications for the Future.

Patients suffering from rheumatologic diseases are known to have an increased risk for cardiovascular disease (CVD). Although the pathological mechanisms behind this excess risk have been increasingly better understood, there still seems to be a general lack of consensus in early detection and treatment of endothelial dysfunction and CVD risk in patients suffering from rheumatologic diseases and in particular in those who haven't yet shown symptoms of CVD. Traditional CVD prediction scores, such as Systematic Coronary Risk Evaluation (SCORE), Framingham, or PROCAM Score have been proposed as valid assessment tools of CVD risk in the general population. However, these risk calculators developed for the general population do not factor in the effect of the inflammatory burden, as well as other factors that can increase CVD risk in patients with rheumatic diseases, such as glucocorticoid therapy, abnormal lipoprotein function, endothelial dysfunction or accelerated atherosclerosis. Thus, their sole use could lead to underestimation of CVD risk in patients with rheumatic diseases. Therefore, there is a need for new biomarkers which will allow a valid and early assessment of CVD risk. In recent years, different research groups, including ours, have examined the value of different CVD risk factors such as carotid sonography, carotid-femoral pulse wave velocity, flow-mediated arterial dilation and others in the assessment of CVD risk. Moreover, various novel CVD laboratory markers have been examined in the setting of autoimmune diseases, such as Paraoxonase activity, Endocan and Osteoprotegerin. Dyslipidemia in rheumatoid arthritis (RA) is for instance better quantified by lipoproteins and apolipoproteins than by cholesterol levels; screening as well as pre-emptive carotid sonography hold promise to identify patients earlier, when prophylaxis is more likely to be effective. The early detection of subtle changes indicating CVD in asymptomatic patients has been facilitated through improved imaging methods; the inclusion of artificial intelligence (AI) shows promising results in more recent studies. Even though the pathophysiology of coronary artery disease in patients with autoimmune rheumatic diseases has been examined in multiple studies, as we continuously gain an increased understanding of this comorbidity, particularly in subclinical cases we still seem to fail in the stratification of who really is at risk-and who is not. A the time being, a multipronged and personalized approach of screening patients for traditional CVD risk factors, integrating modern imaging and further CV diagnostic tools and optimizing treatment seems to be a solid approach. There is promising research on novel biomarkers, likewise, methods using artificial intelligence in imaging provide encouraging data indicating possibilities of risk stratification that might become gold standard in the near future. The present review concentrates on showcasing the newest findings concerning CVD risk in patients with rheumatologic diseases and aims to evaluate screening methods in order to optimize CVD risk evaluation and thus avoiding underdiagnosis and undertreatment, as well as highlighting which patient groups are most at risk.

Clinical spectrum time course in non-Asian patients positive for anti-MDA5 antibodies.

OBJECTIVES: To define the clinical spectrum time-course and prognosis of non-Asian patients positive for anti-MDA5 antibodies. METHODS: We conducted a multicentre, international, retrospective cohort study. RESULTS: 149 anti-MDA5 positive patients (median onset age 53 years, median disease duration 18 months), mainly females (100, 67%), were included. Dermatomyositis (64, 43%) and amyopathic dermatomyositis (47, 31%), were the main diagnosis; 15 patients (10%) were classified as interstitial pneumonia with autoimmune features (IPAF) and 7 (5%) as rheumatoid arthritis. The main clinical findings observed were myositis (84, 56%), interstitial lung disease (ILD) (108, 78%), skin lesions (111, 74%), and arthritis (76, 51%). The onset of these manifestations was not concomitant in 74 cases (50%). Of note, 32 (21.5%) patients were admitted to the intensive care unit for rapidly progressive-ILD, which occurred in median 2 months from lung involvement detection, in the majority of cases (28, 19%) despite previous immunosuppressive treatment. One-third of patients (47, 32% each) was ANA and anti-ENA antibodies negative and a similar percentage was anti-Ro52 kDa antibodies positive. Non-specific interstitial pneumonia (65, 60%), organising pneumonia (23, 21%), and usual interstitial pneumonia-like pattern (14, 13%) were the main ILD patterns observed. Twenty-six patients died (17%), 19 (13%) had a rapidly progressive-ILD. CONCLUSIONS: The clinical spectrum of the anti-MDA5 antibodies-related disease is heterogeneous. Rapidly-progressive ILD deeply impacts the prognosis also in non-Asian patients, occurring early during the disease course. Anti-MDA5 antibody positivity should be considered even when baseline autoimmune screening is negative, anti-Ro52 kDa antibodies are positive, and radiology findings show a NSIP pattern.

Development and Validation of Rheumatoid Arthritis Disease Activity Indices Including HandScan (Optical Spectral Transmission) Scores.

OBJECTIVE: To develop and validate a composite rheumatoid arthritis (RA) disease activity index using optical spectral transmission (OST) scores obtained with the HandScan, replacing tender and swollen joint counts. METHODS: RA patients from a single center routinely undergoing HandScan measurements with at least 1 concurrent OST score and Disease Activity Score in 28 joints (DAS28) were included. Data were extracted from medical records. Linear regression analyses with the DAS28 as the outcome were performed to create a disease activity index (DAS-OST). OST score, erythrocyte sedimentation rate (ESR), and patient global assessment (PtGA) visual analog scale (VAS), sex, age, disease duration, and rheumatoid factor status were evaluated as independent variables. Final models were derived based on the statistical significance of coefficients and model fit. Of the data, two-thirds were used for development and one-third for validation; external validation was performed in a cohort from another center. Agreement between DAS-OST and DAS28 was assessed using the Bland-Altman plot method and intraclass correlation coefficient (ICC). Diagnostic value of the DAS-OST was determined for established definitions of remission, low disease activity (LDA), and high disease activity (HDA). RESULTS: Data of 3,358 observations from 1,505 unique RA patients were extracted. DAS-OST was defined as: -0.44 + OST × 0.03 + male × -0.11 + LN(ESR) × 0.77 + PtGA VAS × 0.03. The ICCs between DAS-OST and DAS28 were 0.88 (95% confidence interval [95% CI] 0.87-0.90) and 0.82 (95% CI 0.75-0.86) and measurement errors were 0.58 and 0.87 in internal and external validation, respectively. Sensitivity for remission, LDA, and HDA was 79%, 91%, and 43%, respectively, and specificity was 92%, 80%, and 96% in external validation. CONCLUSION: Using the HandScan, RA disease activity can be accurately estimated if combined with ESR, PtGA VAS, and sex into a disease activity index (DAS-OST).

The clinical phenotype of systemic sclerosis patients with anti-PM/Scl antibodies: results from the EUSTAR cohort.

OBJECTIVE: To evaluate clinical associations of anti-PM/Scl antibodies in patients with SSc in a multicentre international cohort, with particular focus on unresolved issues, including scleroderma renal crisis (RC), malignancies, and functional outcome of interstitial lung disease (ILD). METHODS: (1) Analysis of SSc patients from the EUSTAR database: 144 anti-PM/Scl+ without SSc-specific autoantibodies were compared with 7202 anti-PM/Scl-, and then to 155 anti-Pm/Scl+ with SSc-specific antibodies. (2) Case-control study: additional data were collected for 165 anti-PM/Scl+ SSc patients (85 from the EUSTAR registry) and compared with 257 anti-PM/Scl- SSc controls, matched for sex, cutaneous subset, disease duration and age at SSc onset. RESULTS: Patients with isolated anti-PM/Scl+, as compared with anti-Pm/Scl-, had higher frequency of muscle involvement, ILD, calcinosis and cutaneous signs of DM, but similar frequency of SRC and malignancies (either synchronous with SSc onset or not). The presence of muscle involvement was associated with a more severe disease phenotype. Although very frequent, ILD had a better functional outcome in cases than in controls. In patients with both anti-PM/Scl and SSc-specific antibodies, a higher frequency of typical SSc features than in those with isolated anti-PM/Scl was observed. CONCLUSION: The analysis of the largest series of anti-PM/Scl+ SSc patients so far reported helps to delineate a specific clinical subset with muscle involvement, cutaneous DM, calcinosis and ILD characterized by a good functional outcome. SRC and malignancies do not seem to be part of this syndrome.