Multi-Dimensional Validation of the Integration of Syntactic and Semantic Distance Measures for Clustering Fibromyalgia Patients in the Rheumatic Monitor Big Data Study.

This study primarily aimed at developing a novel multi-dimensional methodology to discover and validate the optimal number of clusters. The secondary objective was to deploy it for the task of clustering fibromyalgia patients. We present a comprehensive methodology that includes the use of several different clustering algorithms, quality assessment using several syntactic distance measures (the Silhouette Index (SI), Calinski-Harabasz index (CHI), and Davies-Bouldin index (DBI)), stability assessment using the adjusted Rand index (ARI), and the validation of the internal semantic consistency of each clustering option via the performance of multiple clustering iterations after the repeated bagging of the data to select multiple partial data sets. Then, we perform a statistical analysis of the (clinical) semantics of the most stable clustering options using the full data set. Finally, the results are validated through a supervised machine learning (ML) model that classifies the patients back into the discovered clusters and is interpreted by calculating the Shapley additive explanations (SHAP) values of the model. Thus, we refer to our methodology as the clustering, distance measures and iterative statistical and semantic validation (CDI-SSV) methodology. We applied our method to the analysis of a comprehensive data set acquired from 1370 fibromyalgia patients. The results demonstrate that the K-means was highly robust in the syntactic and the internal consistent semantics analysis phases and was therefore followed by a semantic assessment to determine the optimal number of clusters (k), which suggested k = 3 as a more clinically meaningful solution, representing three distinct severity levels. the random forest model validated the results by classification into the discovered clusters with high accuracy (AUC: 0.994; accuracy: 0.946). SHAP analysis emphasized the clinical relevance of "functional problems" in distinguishing the most severe condition. In conclusion, the CDI-SSV methodology offers significant potential for improving the classification of complex patients. Our findings suggest a classification system for different profiles of fibromyalgia patients, which has the potential to improve clinical care, by providing clinical markers for the evidence-based personalized diagnosis, management, and prognosis of fibromyalgia patients.

Effect of Secukinumab and Tumor Necrosis Factor Inhibitors on Humoral Response to BNT162b2 mRNA Vaccine in Patients With Spondyloarthritis Compared to Immunocompetent Controls.

OBJECTIVE: To assess the humoral response to the BNT162b2 mRNA vaccine among patients with spondyloarthritis (SpA) receiving secukinumab (SEC) compared to those receiving tumor necrosis factor inhibitors (TNFi) and immunocompetent controls. METHODS: Consecutive patients with psoriatic arthritis or axial SpA receiving SEC (n = 37) or TNFi (monotherapy, n = 109; + methotrexate [MTX], n = 16), immunocompetent controls (n = 122), and patients with rheumatoid arthritis (RA) receiving TNFi therapy (controls, n = 50) were vaccinated with 2 or 3 doses of the BNT162b2 vaccine. We evaluated humoral response, adverse events, and disease activity, and monitored for breakthrough coronavirus disease 2019 (COVID-19) postvaccination. RESULTS: The 2-dose vaccine regimen induced a comparable seropositive response in all study groups. S1/S2 antibody titers (in binding antibody units/mL; mean [SD]) were higher in the SEC group vs the TNFi + MTX-SpA and TNFi-RA groups (192.5 [68.4] vs 104.6 [46.9], P < 0.001, and 143.1 [81.9], P = 0.004). After 6 months, 96.3%, 96.6%, and 80.9% of the SEC, immunocompetent, and TNFi monotherapy-SpA groups (P = 0.10), respectively; 66.7% of the TNFi + MTX-SpA group (P = 0.03); and 63% of the TNFi-RA group (P = 0.004) remained seropositive. S1/S2 antibody titer decline was steeper in the TNFi groups than the SEC group. After the third dose, 100% of the SpA and immunocompetent and 88.9% of the TNFi-RA (P = 0.25) groups were seropositive. Rate of breakthrough COVID-19 infection was higher in the TNFi groups than in the SEC group (36-37.5% vs 10.8%). No significant between-group differences were observed for postvaccination disease activity and adverse events. CONCLUSION: SEC did not interfere with the immunogenic response to BNT162b2 vaccine in patients with SpA; however, TNFi therapy was associated with lower S1/S2-antibody titers, faster decline, and higher rate of breakthrough infections.

Real-Life Utilization of Criteria Guidelines for Diagnosis of Cardiac Sarcoidosis (CS).

Despite the increasing recognition of cardiac involvement in systemic sarcoidosis, the diagnosis of cardiac sarcoidosis (CS) remains challenging. Our aim is to present a comprehensive, retrospective case series of CS patients, focusing on the current diagnostic guidelines and management of this life-threatening condition. In our case series, patient data were collected retrospectively, including hospital admission records and rheumatology and cardiology clinic visit notes, detailing demographic, clinical, laboratory, pathology, and imaging studies, as well as cardiac devices and prescribed medications. Cases were divided into definite and probable CS based on the 2014 Heart Rhythm Society guidelines as well as presumed CS based on imaging criteria and clinical findings. Overall, 19 CS patients were included, 17 of whom were diagnosed with probable or presumed CS based on cardiac magnetic resonance imaging (CMR) and/or cardiac positron emission tomography using 18F-Fluorodeoxyglucose (PET-FDG) without supporting endomyocardial biopsy (EMB). The majority of CS patients were male (53%), with a mean age of 52.9 ± 11.8, with CS being the initial manifestation of sarcoidosis in 63% of cases. Most patients presented with high-grade AVB (63%), followed by heart failure (42%) and ventricular tachyarrhythmia (VT) (26%). This case series highlights the significance of utilizing updated diagnostic criteria relying on CMR and PET-FDG given that cardiac involvement can be the initial manifestation of systemic sarcoidosis, requiring prompt diagnosis and treatment to prevent morbidity and mortality.

High percentages and activity of synovial fluid NK cells present in patients with advanced stage active Rheumatoid Arthritis.

Rheumatoid Arthritis (RA) causes chronic inflammation of joints. The cytokines TNFα and IFNγ are central players in RA, however their source has not been fully elucidated. Natural Killer (NK) cells are best known for their role in elimination of viral-infected and transformed cells, and they secrete pro-inflammatory cytokines. NK cells are present in the synovial fluids (SFs) of RA patients and are considered to be important in bone destruction. However, the phenotype and function of NK cells in the SFs of patients with erosive deformative RA (DRA) versus non-deformative RA (NDRA) is poorly characterized. Here we characterize the NK cell populations present in the blood and SFs of DRA and NDRA patients. We demonstrate that a distinct population of activated synovial fluid NK (sfNK) cells constitutes a large proportion of immune cells found in the SFs of DRA patients. We discovered that although sfNK cells in both DRA and NDRA patients have similar phenotypes, they function differently. The DRA sfNK secrete more TNFα and IFNγ upon exposure to IL-2 and IL-15. Consequently, we suggest that sfNK cells may be a marker for more severely destructive RA disease.

A high and equal prevalence of the Q703K variant in NLRP3 patients with autoinflammatory symptoms and ethnically matched controls.

OBJECTIVES: Cryopyrin associated periodic syndromes (CAPS) comprise a spectrum of autoinflammatory disorders of varying severity caused by mutations in the NLRP3 gene. The NLRP3-Q703K allele has been reported both as a functional polymorphism and as a low penetrance mutation. METHODS: To describe the clinical phenotype of subjects with the Q703K allele and to report the frequency of this allele among patients with autoinflammatory symptoms and healthy controls. To this end, a cohort of 10 ethnically-matched controls per each Q703K-carrying patient, was composed. RESULTS: Ninety patients suspected of harboring a systemic autoinflammatory disease (SAID), exclusive of FMF, were referred to our center for genotyping between 2012 and 2015. Fourteen of them (15.5%) were found to carry the Q703K allele, compared to 22 of 130 (16.9%) healthy, ethnically matched controls. CONCLUSIONS: The similar carrier rate of the NLRP3-Q703K allele among patients with manifestations of a SAID and an ethnically matched control group suggest that this variant, does not determine the clinical phenotype. This reiterates the importance of testing a control group to avoid erroneously attributing a causative role to a gene polymorphism.

Vasculitis in the autoinflammatory diseases.

PURPOSE OF REVIEW: This article addresses the prevalence and relationship between autoinflammatory diseases and vasculitis. RECENT FINDINGS: Autoimmune diseases (AIDs) are a group of syndromes characterized by episodes of unprovoked inflammation due to dysregulation of the innate immune system. Despite the common occurrence of rashes and other skin lesions in these diseases, vasculitis is reported in only a few. On the other hand, neutrophilic dermatoses are more prevalent. Large vessel vasculitis is reported in patients with Behcet's and Blau's syndromes. Small and medium size vasculitides are reported in familial Mediterranean fever mainly as Henoch-Schonlein purpura and polyarteritis nodosa, respectively. It is rarely described in hyper IgD with periodic fever syndrome, cryopyrin associated periodic syndromes, TNF receptor-associated periodic syndrome, deficiency of interleukin-1 receptor antagonist and pyoderma gangrenosum and acne syndrome. In most AID where bones and skin are mainly involved (CRMO, Majeed syndrome, Cherubism and DITRA) - vasculitis has not been described at all. In AID small vessel vasculitis affects mainly the skin with no involvement of internal organs. SUMMARY: In AID, neutrophilic dermatoses are more common and prominent than vasculitis. This may reflect a minor role for interleukin-1 in the pathogenesis of vasculitis. The rarity of vasculitis in AID suggests that in most reported cases its occurrence has been probably coincidental rather than being an integral feature of the disease.

Intracardiac mass as initial cardiac manifestation of Behçet's disease: think before you cut.

Behçet's disease (BD) is a chronic multisystemic inflammatory disorder. Cardiac abnormalities including intracardiac thrombi have been described in up to 16% of cases. The clinical presentation of cardiac complications in BD may include fever, dyspnea, chest pain, hemoptysis, and edema. We present 2 cases of patients who underwent surgical excision of intracardiac masses thought to be intracardiac malignancies. Further pathological and clinical evaluation established intracardiac inflammatory masses due to BD as the final diagnosis. As intracardiac masses may be the presenting manifestation of BD, it is crucial for echocardiographers to consider BD in the differential diagnosis. A careful history and physical exam looking for signs and symptoms of BD is critical before considering surgical excision of unexplained intracardiac masses. If the final diagnosis is BD anti-inflammatory therapy should be considered the basis of treatment.

Myasthenia gravis appearing 18 years after resection of benign thymoma with subsequent limbic encephalitis.

Thymoma is associated with multiple autoimmune disorders, most commonly myasthenia gravis (MG). However, symptomatic MG may first present following thymectomy. We report an unusual patient with paraneoplastic limbic encephalitis diagnosed a few months after total thymectomy for asymptomatic thymoma, followed 18 years later by the onset of symptomatic MG without evidence of tumor recurrence.

Renal artery stenosis with significant proteinuria may be reversed after nephrectomy or revascularization in patients with the antiphospholipid antibody syndrome: a case series and review of the literature.

Renal artery stenosis (RAS) is a disease which might present as hypertension, renal insufficiency or proteinuria and even as nephrotic syndrome. While 90% of cases are secondary to atherosclerosis, the rest of the cases are usually related to fibromuscular dysplasia. Recently, RAS has also been documented in patients with the antiphospholipid syndrome (APS). Although cases of nephrotic syndrome induced by RAS have been published, cases of patients with APS and nephrotic syndrome attributed to RAS were not reported in the literature. In this paper, three young male patients with APS, hypertension and significant proteinuria secondary to RAS are presented. The patients were treated with nephrectomy or revascularization in addition to prior treatment with warfarin, with improvement of the hypertension and the proteinuria. The relationship between renal artery stenosis, nephrotic range proteinuria and APS is reviewed. We suggest that renal artery stenosis should be included in the differential diagnosis of the nephrotic syndrome and that APS should be included in the differential diagnosis of renal artery stenosis especially in young male patients with proteinuria.