Validation of claims-based algorithms for rheumatoid arthritis in Japan: Results from the VALIDATE-J study.

AIM: Validity of Algorithms in Large Databases: Infectious Diseases, Rheumatoid Arthritis, and Tumor Evaluation in Japan (VALIDATE-J) study examined algorithms for identifying rheumatoid arthritis (RA) in Japanese claims data. METHODS: VALIDATE-J was a multicenter, cross-sectional retrospective study. Disease-identifying algorithms were used to detect RA diagnosed between January 2012 and December 2016 using claims data from two Japanese hospitals. An RA diagnosis was confirmed using one of four gold standard definitions. Positive predictive values (PPVs) were calculated for prevalent (regardless of baseline RA-free period) and incident (preceded by a 12-month RA-free period) cases. RESULTS: Of patients identified using claims-based algorithms, a random sample of 389 prevalent and 134 incident cases of RA were included. Cases identified by an RA diagnosis, no diagnosis of psoriasis, and treatment with any disease-modifying antirheumatic drugs (DMARDs) resulted in the highest PPVs versus other claims-based treatment categories (29.0%-88.3% [prevalent] and 41.0%-78.2% [incident]); cases identified by an RA diagnosis, no diagnosis of psoriasis, and glucocorticoid-only treatment had the lowest PPVs. Across claims-based algorithms, PPVs were highest when a physician diagnosis or decision by adjudicators (confirmed and probable cases) was used as the gold standard and were lowest when American College of Rheumatology/European Alliance of Associations for Rheumatology 2010 criteria were applied. PPVs of claims-based algorithms for RA in patients aged ≥66 years were slightly higher versus a USA Medicare population (maximum PPVs of 95.0% and 88.9%, respectively). CONCLUSION: VALIDATE-J demonstrated high PPVs for most claims-based algorithms for diagnosis of prevalent and incident RA using Japanese claims data. These findings will help inform appropriate RA definitions for future claims database research in Japan.

Validity of claims-based diagnoses for infectious diseases common among immunocompromised patients in Japan.

BACKGROUND: To validate Japanese claims-based disease-identifying algorithms for herpes zoster (HZ), Mycobacterium tuberculosis (MTB), nontuberculous mycobacteria infections (NTM), and Pneumocystis jirovecii pneumonia (PJP). METHODS: VALIDATE-J, a multicenter, cross-sectional, retrospective study, reviewed the administrative claims data and medical records from two Japanese hospitals. Claims-based algorithms were developed by experts to identify HZ, MTB, NTM, and PJP cases among patients treated 2012-2016. Diagnosis was confirmed with three gold standard definitions; positive predictive values (PPVs) were calculated for prevalent (regardless of baseline disease-free period) and incident (preceded by a 12-month disease-free period for the target conditions) cases. RESULTS: Of patients identified using claims-based algorithms, a random sample of 377 cases was included: HZ (n = 95 [55 incident cases]); MTB (n = 100 [58]); NTM (n = 82 [50]); and PJP (n = 100 [84]). PPVs ranged from 67.4-70.5% (HZ), 67.0-90.0% (MTB), 18.3-63.4% (NTM), and 20.0-45.0% (PJP) for prevalent cases, and 69.1-70.9% (HZ), 58.6-87.9% (MTB), 10.0-56.0% (NTM), and 22.6-51.2% (PJP) for incident cases, across definitions. Adding treatment to the algorithms increased PPVs for HZ, with a small increase observed for prevalent cases of NTM. CONCLUSIONS: VALIDATE-J demonstrated moderate to high PPVs for disease-identifying algorithms for HZ and MTB using Japanese claims data.

Infrequent Thrombotic Complications in Japanese Patients with Warm Autoimmune Hemolytic Anemia.

Objective Patients with autoimmune hemolytic anemia (AIHA) are considered to be at an increased risk of thrombosis, and prophylaxis for venous thromboembolism (VTE) is often recommended. However, the occurrence of thrombosis in Asian patients has not been specifically studied. Thrombotic complications and features of Japanese warm AIHA (WAIHA) patients were studied to see if Japanese patients were at an increased risk of thrombosis and should receive prophylaxis for VTE. Patients and Methods Forty-seven consecutive patients with warm WAIHA were retrospectively studied. Twenty-nine patients were diagnosed as primary cases and 18 as secondary cases, and 10 patients were diagnosed with Evans syndrome. Results No patient presented with thrombosis, and over a median observation period of 15 months, 3 patients had ischemic cerebral vascular accidents. However, all three of those patients had other known risks for thrombosis, with only one taking thrombotic prophylaxis. No venous thrombosis occurred in any patients during the follow-up period. There was no mortality associated with thrombosis. D-dimer levels were often elevated in patients with WAIHA, indicating that the coagulation was activated in a considerable number of patients, but not to such a level as to be associated with clinically overt thrombosis. Conclusion Thrombotic complications occur infrequently in Japanese WAIHA patients, and these individuals do not appear to be at a particularly increased risk of thrombosis because of WAIHA. The indication of VTE prophylaxis should be determined individually, considering other risks.

Transient Pseudothrombocytopenia Detected 8 Months After COVID-19 Vaccination.

Pseudothrombocytopenia is an in vitro phenomenon of platelet aggregation due to conformational changes and exposure of cryptic antigens on the platelet surface caused by anticoagulants, leading to the aggregation of platelets and falsely lower automated platelet counts. Although it has no clinical relevance, it can lead to unnecessary fear, diagnostic errors, or unnecessary tests and interventions when unrecognized. Pseudothrombocytopenia was detected in a 25-year-old woman 8 months after the second dose of mRNA COVID-19 vaccine, BNT162b2. The pseudothrombocytopenia was transient and the duration was shorter than 3 months. As pseudothromobocytopenia is not detected unless blood is drawn for other objectives, it is difficult to determine its true occurrence among recipients of vaccines. This case shows that pseudothrombocytopenia may develop transiently even months after COVID-19 vaccination and should be considered when thrombocytopenia is found in recipients of the vaccine to avoid unnecessary fear, diagnostic errors, or unnecessary tests and interventions.

Validity of claims-based algorithms for selected cancers in Japan: Results from the VALIDATE-J study.

PURPOSE: Real-world data from large administrative claims databases in Japan have recently become available, but limited evidence exists to support their validity. VALIDATE-J validated claims-based algorithms for selected cancers in Japan. METHODS: VALIDATE-J was a multicenter, cross-sectional, retrospective study. Disease-identifying algorithms were used to identify cancers diagnosed between January or March 2012 and December 2016 using claims data from two hospitals in Japan. Positive predictive values (PPVs), specificity, and sensitivity were calculated for prevalent (regardless of baseline cancer-free period) and incident (12-month cancer-free period; with claims and registry periods in the same month) cases, using hospital cancer registry data as gold standard. RESULTS: 22 108 cancers were identified in the hospital claims databases. PPVs (number of registry cases) for prevalent/incident cases were: any malignancy 79.0% (25 934)/73.1% (18 119); colorectal 84.4% (3519)/65.6% (2340); gastric 87.4% (3534)/76.8% (2279); lung 88.1% (2066)/79.9% (1636); breast 86.4% (4959)/59.9% (3185); pancreatic 87.1% (582)/80.4% (508); melanoma 48.7% (46)/42.9% (36); and lymphoma 83.6% (1457)/77.8% (1035). Specificity ranged from 98.3% to 100% (prevalent)/99.5% to 100% (incident); sensitivity ranged from 39.1% to 67.6% (prevalent)/12.5% to 31.4% (incident). PPVs of claims-based algorithms for several cancers in patients ≥66 years of age were slightly higher than those in a US Medicare population. CONCLUSIONS: VALIDATE-J demonstrated high specificity and modest-to-moderate sensitivity for claims-based algorithms of most malignancies using Japanese claims data. Use of claims-based algorithms will enable identification of patient populations from claims databases, while avoiding direct patient identification. Further research is needed to confirm the generalizability of our results and applicability to specific subgroups of patient populations.

Reticulocyte Hemoglobin Equivalent in Patients with Idiopathic Warm Autoimmune Hemolytic Anemia: Implication in the Development of Macrocytosis.

OBJECTIVE: Patients with warm autoimmune hemolytic anemia (WAIHA) present with anemia that is highly heterogeneous, and often have macrocytic anemia with inappropriately elevated mean corpuscular volume (MCV). The goal of this retrospectivecase study is to elucidate the characteristics of anemia in patients with idiopathic WAIHA. PROCEDURES: The hematological parameters were analyzed by automated hematology analyzers in 19 consecutive patients with idiopathic WAIHA. Thecontent of hemoglobin (Hb) in the reticulocytes was assessed as reticulocyte Hb equivalent (RET-He). Relevant laboratory data and medical records were retrospectively studied. RESULTS: The median MCV was 102.7 fL and ten patients had macrocytic anemia with MCV above 100 fL. There was a significant correlation between the percentage of reticulocytes and MCV. The median RET-He value was 35.9 pg, and the reticulocytes of patients with higher MCV had higher RET-He. There was a significant correlation between red cell volume distribution width (RDW) andMCV, while the association between RDW and RET-He was not significant. Red blood cell agglutination was not seen in any of the patients. Relative folate deficiency was implied to contribute to the increased Hb content in the reticulocytes of WAIHA patients. CONCLUSION: Reticulocytes in WAIHA patients often contain more Hb than normal reticulocytes and become inappropriately large, possibly due to relative folate deficiency. Elevated MCV in WAIHA patients is due to the increase in both the number and the Hb content of reticulocytes.

Low level of hemoglobin A1c and the increased incidence of herpes zoster: longitudinal study.

Little is known about the association between glycemic status and herpes zoster. The aim of this study was to evaluate whether glycemic status, including both high and low hemoglobin A1c(HbA1c), is associated with subsequent herpes zoster. We conducted a retrospective longitudinal study in a large teaching hospital in Tokyo, Japan, from 2005 to 2016. We included all participants who underwent voluntary health check-ups at the hospital. Our primary outcome was the incidence of herpes zoster in groups of individuals stratified by HbA1c levels, which were compared using the generalized estimating equation (GEE), adjusting for participants' demographic characteristics, social history, body mass index, and comorbidities. A total of 81,466 participants were included in this study. The mean age (standard deviation) was 46.5 (12.1), and 39,643 (48.7%) participants were male. Among them, 1751 (2.1%) were diagnosed with diabetes prior to their first visits. After a median follow-up of 1784 [interquartile range (IQR), 749-3150] days, 673 (0.8%) participants developed herpes zoster. The incidence of herpes zoster was 1.45 per 1000 person-years. Compared with the reference group (HbA1c of 5.0-6.4%), the lowest HbA1c group (HbA1c of < 5.0%) had a significantly higher adjusted odds ratio (OR) (OR 1.63; 95% confidence interval (CI), 1.07-2.48) of developing herpes zoster. The group with an HbA1c of ≥ 9.5% had a higher but nonsignificant OR than the reference group (OR 2.15; 95% CI, 0.67-6.94). Our longitudinal study demonstrated that individuals in the lowest (< 5.0%) HbA1c group had a significantly higher risk of developing herpes zoster than the reference group (HbA1c of 5.0-6.4%) after adjusting for covariates.

Hyperferritinemia: causes and significance in a general hospital.

OBJECTIVE: To elucidate conditions which cause elevation of the serum ferritin, extent of the elevation in each condition, and clinical relevance of hyperferritinemia in general practice. METHODS: We retrospectively studied medical records of all patients who had at least one serum ferritin measurement above 500 µg L-1. Patients who had a marked elevation of the serum ferritin over 10,000 µg L-1 were studied separately. RESULTS: We studied 1394 patients to identify the etiologies of hyperferritinemia. Median serum ferritin level was 1024 µg L-1 and 49.2% had ferritin levels of 501-1000 µg L-1. The most frequent cause of hyperferritinemia was non-human immunodeficiency virus infection followed by solid tumor, liver dysfunction, renal failure, and hematological malignancy. The distributions of the causes were different among groups stratified by the ferritin level. Forty-one percent had multiple causes and there was a tendency that the more underlying causes a patient had, the higher the ferritin level. Each condition led to a wide range of the ferritin level, and some patients could present with marked hyperferritinemia. Seventy percent of 111 patients with marked hyperferritinemia had multiple etiologies and a variety of diseases could lead to marked hyperferritinemia by themselves. DISCUSSION: Patients with hyperferritinemia frequently had multiple conditions. The level of the serum ferritin was determined by the underlying conditions to a certain extent; however, the variation was significant. While patients with marked hyperferritinemia mostly had multiple underlying causes, various diseases could cause hyperferritinemia by themselves. CONCLUSION: Hyperferritinemia is associated with both etiology and the number of underlying causes.

Simultaneous Presentation of Giant Cell Arteritis and Myelodysplastic Syndrome in an Elderly Japanese Man.

An 81-year-old Japanese man presented with constitutional symptoms and anemia and was diagnosed with giant cell arteritis (GCA) and myelodysplastic syndrome (MDS) simultaneously. His symptoms and anemia improved promptly with steroids; however, the MDS rapidly progressed to overt leukemia. While MDS patients are at an increased risk of autoimmune diseases, an association with GCA has rarely been reported. This case illustrates the importance of considering GCA as a cause of anemia in elderly patients if MDS is already diagnosed, even in countries where the prevalence of GCA is very low. The simultaneous development of GCA and MDS suggests a common pathogenetic link between these two diseases.

The Relationship Between Mean Platelet Volume and Fasting Plasma Glucose and HbA1c Levels in a Large Cohort of Unselected Health Check-Up Participants.

BACKGROUND: Larger platelets are more active and mean platelet volume (MPV) is an indicator of platelet activation and an independent risk factor of cardiovascular diseases. While MPV is reported to be higher in diabetic patients, the relationship between MPV and glycemic parameters in general population remains inconclusive. METHODS: In this cross-sectional study, we studied relationship between MPV and fasting plasma glucose (FPG) and HbA1c levels in 38,204 unselected participants of general health check-up aged 20 years or older in the year of 2014 who were considered to be representative of the general population. Individuals with known diabetes, coronary artery disease and/or cerebrovascular disease who were on drug therapy and those with platelet counts below 100 × 109/L or above 400 × 109/L were excluded. RESULTS: The mean age of the individuals was 52.3 ± 12.1 years and 46.1% were male. There were positive associations between MPV and both FPG (r = 0.066; P < 0.001) and HbA1c (r = 0.025; P < 0.001) levels when all individuals were analyzed as a whole. While the association was only marginal in individuals with HbA1c levels below 6.5% (r = 0.009; P = 0.068), it was significant in those with HbA1c ≥ 6.5% (r = 0.138; P < 0.001). When the individuals were categorized into four groups according to the HbA1c values: HbA1c < 5.5%, 5.5% ≤ HbA1c < 6.0%, 6.0% ≤ HbA1c < 6.5%, and HbA1c ≥ 6.5%, the mean MPV was virtually same among groups with HbA1c level < 6.5% and that of the individuals with HbA1c ≥ 6.5 was significantly higher than groups with lower HbA1c levels. Multivariate analyses adjusted with age and sex showed the same results. CONCLUSION: FPG and HbA1c appeared to be associated with MPV in unselected health check-up participants; however, the association between glycemic state and MPV was apparent only in individuals with impaired glycemic control and only marginal in those with normal glycemic control. The clinical significance of the associations warrants further study.

Iron Deficiency Anemia Due to the Long-term Use of a Proton Pump Inhibitor.

A 52-year-old man who had been taking omeprazole, a proton pump inhibitor (PPI), for 25 years developed iron deficiency anemia. An evaluation of the entire gastrointestinal tract did not reveal any possible causes of gastrointestinal blood loss. The cause of the iron deficiency was considered to be a reduction in gastrointestinal iron absorption in association with the reduced secretion of gastric acid due to PPI use. This case demonstrates that long-term PPI use for as long as 25 years may cause iron deficiency anemia and should be considered in the differential diagnosis of iron deficiency anemia in long-term PPI users.

Myelodysplastic Syndrome Developing Presacral Extramedullary Hematopoiesis with Atypical MRI Findings.

A 64-year-old woman was diagnosed to have refractory cytopenia with multilineage dysplasia (RCMD) including an increased number of sideroblasts in the bone marrow (BM). Computed tomography (CT) revealed a presacral mass which showed iso- or high-intensity signals according to T1-weighted and hypo-intensity signals on T2-weighted magnetic resonance imaging (MRI). CT-guided biopsy revealed the presence of hematopoietic tissue with features that correlated with the BM findings. While the formation of extramedullary hematopoiesis in the presacral area is rare, it is important to differentiate it from other parasacral tumors even though such differentiation is often difficult. This patient demonstrated atypical MRI signals possibly due to an increase in the cellular iron content of the erythroid precursors.

Overlap of IgG4-related Disease and Multicentric Castleman's Disease in a Patient with Skin Lesions.

A 59-year-old man presented with multiple dark red erythemas with induration, anemia, and polyclonal hypergammaglobulinemia. A skin biopsy revealed the infiltration of lymphocytes and plasma cells and he was initially diagnosed with multicentric Castleman's disease (MCD). Glucocorticoid treatment was only partially effective. Four years later, the patient's bilateral lacrimal glands gradually became enlarged and a biopsy revealed dense lymphocyte and plasma cell infiltration with an IgG4+/IgG+ plasma cell ratio of 70%. The patient was diagnosed with IgG4-related disease (RD). Rituximab only had a slight effect. This case demonstrates that overlapping features of IgG4-RD and MCD may present in a single patient, which suggests a shared pathogenesis.

Hypertrophic Herpes Simplex Virus Type 1 Infection in a Patient With Acute Myeloid Leukemia.

A 64-year-old woman had a transformation from polycythemia vera to acute myeloid leukemia. While she was treated with azacitidine and prednisolone, a nodule at the left angle of the mouth developed, which was biopsied and diagnosed with hypertrophic herpes simplex virus type 1 (HSV-1) infection. The nodule resolved completely with aciclovir. While HSV type 2 virus occasionally forms mass or tumoral lesions in immunocompromised, especially acquired immunodeficiency syndrome, patients, it is extremely rare that HSV-1 infection leads to similar lesions. The hematological conditions and the therapies given may have contributed to the rare manifestation of HSV-1 infection.

Current cigarette smoking is a reversible cause of elevated white blood cell count: Cross-sectional and longitudinal studies.

While cigarette smoking is a well-recognized cause of elevated white blood cell (WBC) count, studies on longitudinal effect of smoking cessation on WBC count are limited. We attempted to determine causal relationships between smoking and elevated WBC count by retrospective cross-sectional study consisting of 37,972 healthy Japanese adults who had a health check-up between April 1, 2008 and March 31, 2009 and longitudinal study involving 1730 current smokers who had more than four consecutive annual health check-ups between April 1, 2007 and March 31, 2012. In the cross-sectional study, younger age, male gender, increased body mass index, no alcohol habit, current smoking, and elevated C-reactive protein level were associated with elevated WBC count. Among these factors, current smoking had the most significant association with elevated WBC count. In subgroup analyses by WBC differentials, smoking was significantly associated with elevated counts of neutrophils, lymphocytes, monocytes, eosinophils, and basophils. Ex-smoking was not associated with elevated WBC count. In the longitudinal study, both WBC and neutrophil counts decreased significantly in one year after smoking cessation and remained down-regulated for longer than next two years. There was no significant change in either WBC or neutrophil count in those who continued smoking. These findings clearly demonstrated that current smoking is strongly associated with elevated WBC count and smoking cessation leads to recovery of WBC count in one year, which is maintained for longer than subsequent two years. Thus, current smoking is a significant and reversible cause of elevated WBC count in healthy adults.

A Newly Characterized Hemoglobin Variant with a High Oxygen Affinity, Hb Fuchu-II, Presenting with Acute Myocardial Infarction.

A 65-year-old Japanese man presented with acute myocardial infarction (AMI) and polycythemia. Biochemical studies of the patient's hemoglobin (Hb) and the sequencing of his globin genes revealed that the polycythemia was secondary to a high oxygen affinity Hb variant, Hb Fuchu-II. Hb variants with high oxygen affinity can be an additional thrombotic risk factor in older patients and/or those with other risk factors. The patient was diagnosed with hemoglobinopathy after the development of AMI and exemplifies the importance of recognizing such conditions and of taking appropriate prophylactic interventions.

Association of Primary Biliary Cirrhosis-autoimmune Hepatitis Overlap Syndrome with Immune Thrombocytopenia and Graves' Disease.

A 54-year-old woman suffering from pruritus for five years was diagnosed to have Graves' disease and immune thrombocytopenia (ITP) associated with primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome, which was confirmed histologically after a prompt recovery in the platelet count number following steroid therapy. The association between PBC-AIH overlap syndrome and ITP has been rarely reported and the additional association with Graves' disease has not yet been reported. An underlying global derangement of autoimmunity or shared genetic susceptibility was suspected.

Pulmonary Extranodal Marginal Zone Lymphoma with Macroglobulinemia and Mixed Cryoglobulinemia Developed in a Patient with Chronic Hepatitis C.

We report a 65-year-old woman with a chronic hepatitis C virus infection who developed pulmonary extranodal marginal zone lymphoma (EMZL) of mucosa-associated lymphoid tissues complicated with macroglobulinemia and mixed cryoglobulinemia. She was treated with immunochemotherapy which resulted in the reduction of both the tumors and the serum immunoglobulin (Ig) M level. This case exemplifies an extensive stimulation upon immune system with derangement in the production of immunoglobulines associated with EMZL, and suggests that it is necessary to consider the possibility of B-cell lymphoma when IgM paraprotein is detected.