Hypereosinophilic Syndrome with Endomyocarditis: Identification by Next-Generation Sequencing of the JAK2-V617F Mutation.

Hypereosinophilic syndrome requires a peripheral absolute eosinophil count of ≥1.5 × 109 /L with clinical manifestations attributable to peripheral or tissue hypereosinophilia. Clinical manifestations can vary greatly, with the majority of patients relatively asymptomatic and the eosinophilia detected incidentally. However, in a minority of hypereosinophilia cases, they may present with severe lifethreatening organ dysfunction affecting skin, lung, heart, gastrointestinal tract, and nervous system. A case of hypereosinophilia with potentially life-threatening cardiovascular involvement is discussed. Initial laboratory investigations showed an elevated white blood cell count with 60% eosinophils. An endomyocardial biopsy revealed eosinophilic endomyocarditis with granuloma, rare giant cells, and no vasculitis, microorganisms, or malignancy. Her presentation met the criteria for either hypereosinophilic syndrome or eosinophilic granulomatosis with polyangitis. Molecular genetic analysis was negative for myelodysplastic syndrome panel/ Platelet Derived Growth Factor Receptor Beta (PDGFRB) (5q32)/Fibroblast Growth Factor Receptor 1 (FGFR1) Fluorescence In Situ Hybridization (FISH), Feline McDonough Sarcoma-related Tyrosine Kinase 3 (FLT3) Internal Tandem Duplication (ITD) mutation, Calregulin (CALR) exon 9 mutation, and T-cell gene rearrangement/polymerase chain reaction. Bone marrow biopsy revealed a mildly hypocellular marrow with multilineage hematopoiesis,+ megakaryocyte dysplasia, and focal eosinophilia. No excess blasts, no monotypic B-cell population, and no discrete pan T-cell aberrancies were found. Bone marrow cytogenetic studies showed a normal signal pattern for myeloproliferative neoplasms panel/Sec1 Family Domain Containing 2 (SCFD2)-Ligand of Numb Protein-X (LNX)-Platelet-derived Growth Factor Receptor Alpha (PDGFRA) fluorescence in situ hybridization with a normal karyotype of 46 XX. Next-generation sequencing, however, was positive for the JAK2-V617F mutation, a rare molecular abnormality in hypereosinophilic syndrome. The prevalence ranges from approximately 0% to 4%. The JAK2 point mutation leads to aberrant tyrosine phosphorylation and increased cytokine activation. The case demonstrates the complexity and challenging nature of advanced diagnostic opportunities in hypereosinophilia and the potential use, in select subsets, of targeted treatments such as tyrosine kinase inhibitors.

The 2023 ACR/EULAR Classification Criteria for Calcium Pyrophosphate Deposition Disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score >56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

The 2023 ACR/EULAR classification criteria for calcium pyrophosphate deposition disease.

OBJECTIVE: Calcium pyrophosphate deposition (CPPD) disease is prevalent and has diverse presentations, but there are no validated classification criteria for this symptomatic arthritis. The American College of Rheumatology (ACR) and EULAR have developed the first-ever validated classification criteria for symptomatic CPPD disease. METHODS: Supported by the ACR and EULAR, a multinational group of investigators followed established methodology to develop these disease classification criteria. The group generated lists of candidate items and refined their definitions, collected de-identified patient profiles, evaluated strengths of associations between candidate items and CPPD disease, developed a classification criteria framework, and used multi-criterion decision analysis to define criteria weights and a classification threshold score. The criteria were validated in an independent cohort. RESULTS: Among patients with joint pain, swelling, or tenderness (entry criterion) whose symptoms are not fully explained by an alternative disease (exclusion criterion), the presence of crowned dens syndrome or calcium pyrophosphate crystals in synovial fluid are sufficient to classify a patient as having CPPD disease. In the absence of these findings, a score>56 points using weighted criteria, comprising clinical features, associated metabolic disorders, and results of laboratory and imaging investigations, can be used to classify as CPPD disease. These criteria had a sensitivity of 92.2% and specificity of 87.9% in the derivation cohort (190 CPPD cases, 148 mimickers), whereas sensitivity was 99.2% and specificity was 92.5% in the validation cohort (251 CPPD cases, 162 mimickers). CONCLUSION: The 2023 ACR/EULAR CPPD disease classification criteria have excellent performance characteristics and will facilitate research in this field.

Calcium pyrophosphate crystal size and characteristics.

OBJECTIVE: To describe the characteristics of calcium pyrophosphate (CPP) crystal size and morphology under compensated polarized light microscopy (CPLM). Secondarily, to describe CPP crystals seen only with digital enhancement of CPLM images, confirmed with advanced imaging techniques. METHODS: Clinical lab-identified CPP-positive synovial fluid samples were collected from 16 joint aspirates. Four raters used a standardized protocol to describe crystal shape, birefringence strength and color. A crystal expert confirmed CPLM-visualized crystal identification. For crystal measurement, a high-pass linear light filter was used to enhance resolution and line discrimination of digital images. This process identified additional enhanced crystals not seen by raters under CPLM. Single-shot computational polarized light microscopy (SCPLM) provided further confirmation of the enhanced crystals' presence. RESULTS: Of 932 suspected crystals identified by CPLM, 569 met our inclusion criteria, and 293 (51%) were confirmed as CPP crystals. Of 175 unique confirmed crystals, 118 (67%) were rods (median area 3.6 µm2 [range, 1.0-22.9 µm2]), and 57 (33%) were rhomboids (median area 4.8 µm2 [range, 0.9-16.7 µm2]). Crystals visualized only after digital image enhancement were smaller and less birefringent than CPLM-identified crystals. CONCLUSIONS: CPP crystals that are smaller and weakly birefringent are more difficult to identify. There is likely a population of smaller, less birefringent CPP crystals that routinely goes undetected by CPLM. Describing the characteristics of poorly visible crystals may be of use for future development of novel crystal identification methods.

Treatment approaches and adherence to urate-lowering therapy for patients with gout.

Gout is the most common inflammatory arthritis characterized by painful disabling acute attacks. It is caused by hyperuricemia and deposition of urate crystals in and around the joints. Long-standing untreated hyperuricemia can lead to chronic arthritis with joint damage, tophi formation and urate nephropathy. Gout is associated with significant morbidity and health care associated cost. The goal of long-term therapy is to lower the serum urate level to promote dissolution of urate crystals, reduce recurrent acute gout flares, resolve tophi and prevent joint damage. Despite the presence of established gout treatment guidelines and effective medications to manage gout, patient outcomes are often poor. Etiology for these shortcomings is multifactorial including both physician and patient characteristics. Poor adherence to urate-lowering therapy (ULT) is prevalent and is a significant contributor to poor patient outcomes. This article reviews the treatment strategies for the management of hyperuricemia in chronic gout, gaps in quality of care in gout management, factors contributing to poor adherence to ULT and discusses potential interventions to achieve improved gout-related outcomes. These interventions include initiation of prophylactic anti-inflammatory medication when starting ULT, frequent follow-ups, regular serum urate monitoring and improved patient education, which can be achieved through pharmacist- or nurse-assisted programs. Interventions such as these could improve adherence to ULT and, ultimately, result in optimal gout-related outcomes.

Predicting fracture risk in osteoporosis: the use of fracture prediction tools in an osteoporosis clinic population.

BACKGROUND: In the UK, the National Institute for Health and Care Excellence recommends either fracture risk assessment tool (FRAX) or QFracture to estimate the 10 year fracture risk of individuals. However, it is not known how these tools compare in determining risk and subsequent treatment using set intervention thresholds or guidelines. METHODS: The 10 year major osteoporotic (MO) and hip (HI) fracture risks were calculated for 100 women attending osteoporosis clinic in 2010 using FRAX and QFracture, and subsequent agreement to treatment between the tools was looked at using National Osteoporosis Foundation and National Bone Health Alliance thresholds (FRAX-20/3 and QFracture 20/3). We also looked at using these thresholds for QFracture and comparing them with the National Osteoporosis Guideline Group (NOGG) guidelines for FRAX (FRAX-NOGG). RESULTS: The 10 year risk for MO fracture for FRAX was 17.0% (IQR 10.8-24.0) and that of QFracture was 15.8% (IQR 9.5-27.7) (p=0.732). The 10 year risk for HI fracture for FRAX was 5.0% (IQR 2.1-8.9) and that of QFracture was 8.1% (IQR 2.5-21.6) (p<0.001). The agreement between FRAX-20/3 and QFracture-20/3 was greater than the agreement between FRAX-20/3 and FRAX-NOGG or QFracture-20/3 and FRAX-NOGG. CONCLUSIONS: The calculated 10 year risk for MO fracture between FRAX and QFracture was similar, whereas that of HI fracture was significantly different. The agreement to treatment between QFracture-20/3 and FRAX-NOGG was only 45%. Treatment decisions can differ depending on the fracture calculation tool used when coupled with certain intervention thresholds or guidelines.