Effect of Recent Antirheumatic Drug on Features of Rheumatoid Arthritis-Associated Lymphoproliferative Disorders.

OBJECTIVE: In this study, we examine how advancements in novel antirheumatic drugs affect the clinicopathologic features of lymphoproliferative disorder (LPD) in patients with rheumatoid arthritis (RA). METHODS: In this multicenter study across 53 hospitals in Japan, we characterized patients with RA who developed LPDs and visited the hospitals between January 1999 and March 2021. The statistical tools used included Fisher's exact test, the Mann-Whitney U-test, the log-rank test, logistic regression analysis, and Cox proportional hazards models. RESULTS: Overall, 752 patients with RA-associated LPD (RA-LPD) and 770 with sporadic LPD were included in the study. We observed significant differences in the clinicopathologic features between patients with RA-LPD and those with sporadic LPD. Histopathological analysis revealed a high frequency of LPD-associated immunosuppressive conditions. Furthermore, patients with RA-LPD were evaluated based on the antirheumatic drugs administered. The methotrexate (MTX) plus tacrolimus and MTX plus tumor necrosis factor inhibitor (TNFi) groups had different affected site frequencies and histologic subtypes than the MTX-only group. Moreover, MTX and TNFi may synergistically affect susceptibility to Epstein-Barr virus infection. In case of antirheumatic drugs administered after LPD onset, tocilizumab (TCZ)-only therapy was associated with lower frequency of regrowth after spontaneous regression than other regimens. CONCLUSION: Antirheumatic drugs administered before LPD onset may influence the clinicopathologic features of RA-LPD, with patterns changing over time. Furthermore, TCZ-only regimens are recommended after LPD onset.

Exploring the Multifaceted Nexus of Uric Acid and Health: A Review of Recent Studies on Diverse Diseases.

The prevalence of patients with hyperuricemia or gout is increasing worldwide. Hyperuricemia and gout are primarily attributed to genetic factors, along with lifestyle factors like consuming a purine-rich diet, alcohol and/or fructose intake, and physical activity. While numerous studies have reported various comorbidities linked to hyperuricemia or gout, the range of these associations is extensive. This review article focuses on the relationship between uric acid and thirteen specific domains: transporters, genetic factors, diet, lifestyle, gout, diabetes mellitus, metabolic syndrome, atherosclerosis, hypertension, kidney diseases, cardiovascular diseases, neurological diseases, and malignancies. The present article provides a comprehensive review of recent developments in these areas, compiled by experts from the Young Committee of the Japanese Society of Gout and Uric and Nucleic Acids. The consolidated summary serves to enhance the global comprehension of uric acid-related matters.

Evaluation of tetracycline and fluoroquinolone therapy against Japanese spotted fever: Analysis based on individual data from case reports and case series.

OBJECTIVES: Although approximately 40 years have passed since Japanese spotted fever (JSF) was first reported in Japan, its treatment has not yet been standardised. As in other rickettsial infections, tetracycline (TC) is the first-line treatment, but successful instances of fluoroquinolone (FQ) combination therapy in severe cases have been reported. However, the effectiveness of TC plus FQ combined treatment (TC+FQ) remains controversial. Therefore, the antipyretic effect of TC+FQ was evaluated in this study. METHODS: A comprehensive search of published JSF case reports was conducted to extract individual patient data. In cases where it was possible to extract temperature data, after homogenising patient characteristics, time-dependent changes in fever type from the date of the first visit was evaluated for the TC and TC+FQ groups. RESULTS: The primary search yielded 182 cases, with individual data evaluations resulting in a final analysis of 102 cases (84 in the TC group and 18 in the TC+FQ group) that included temperature data. The TC+FQ group had significantly lower body temperature compared with the TC group from Days 3 to 4. CONCLUSIONS: Although TC monotherapy for JSF can eventually result in defervescence, the duration of fever is longer compared with other rickettsial infections such as scrub typhus. The results suggest that the antipyretic effect of TC+FQ was more effective, with a potential shortening of the duration that patients suffer from febrile symptoms.

Estimated excretion and clearance of uric acid as optimal surrogate indices for daily urinary uric acid excretion.

OBJECTIVES: Daily uric acid excretion is an essential index for patients with gout/hyperuricemias. We identified alternative indices most correlated with 24-hour uric acid clearance (Cua 24h) and 24-hour uric acid excretion (Eua 24h) using data from the reference interval of urinary clearance and excretion of urate study. METHODS: The subjects were indoor workers aged 20 to 65 who met the Clinical and Laboratory Standards Institute Guidelines C28-A3c. Alternative indices using spot urine were urine uric acid creatinine ratio, uric acid clearance - creatinine clearance ratio (Cua/Ccr), uric acid excretion - creatinine clearance ratio (Eua/Ccr), estimated uric acid clearance (eCua), and estimated uric acid excretion (eEua). eCua and eEua are the values obtained by multiplying Cua/Ccr and Eua/Ccr by the estimated glomerular filtration rate. RESULTS: The final number of subjects analyzed was 739. Among the indices using spot urine, eCua and eEua showed the highest correlation with Cua 24h and Eua 24h, respectively. Compared with Cua 60min and Eua 60min obtained from 60-minute urine collection, eCua and eEua showed lower root means squared error, lower bias, and significantly higher accuracy of within 30% and within 15%. CONCLUSIONS: The newly proposed eCua and eEua may be appropriate from a practical perspective.

Multifaceted efficacy of caspofungin against fungal infections in COVID-19 patients.

Fungal co-infections of coronavirus disease 2019 (COVID-19) are generally infrequent, but are more common among patients with hematological diseases or severe cases in the intensive care unit (ICU). As fungal infections often carry a high mortality rate, preventing their development is considered important for patients with COVID-19. Caspofungin covers Candida spp. and Aspergillus spp. as causative pathogens of fungal infections associated with COVID-19, and is known to have few side effects among antifungal drugs. Recent studies have shown that caspofungin is expected to inhibit the growth of severe acute respiratory syndrome coronavirus 2. In addition, the inhibitory effects of caspofungin on spleen tyrosine kinase-related intracellular signaling are anticipated to suppress the overproduction of proinflammatory cytokines and immune thrombosis, which are problems in severe COVID-19. Early use of caspofungin in patients with COVID-19 with hematological diseases or in the ICU may help prevent fungal infections and reduce severe cases in COVID-19 patients.

Aseptic Meningitis after Amenamevir Treatment for Herpes Zoster in the First Branch of the Trigeminal Nerve.

Amenamevir has been approved for the treatment of herpes zoster (HZ); however, its therapeutic efficacy against central nervous system (CNS) infection may be insufficient due to its low spinal fluid permeability. We herein report a case of aseptic meningitis in a 91-year-old Japanese man treated with amenamevir for HZ in the trigeminal nerve region. Several cases of CNS infection have been reported in patients receiving amenamevir treatment for HZ. Patients with CNS complications often have skin rashes near the trigeminal region. Thus, we should be alert for signs of CNS infection when administering amenamevir to patients with such rashes.

False positive results in severe acute respiratory coronavirus 2 (SARS-CoV-2) rapid antigen tests for inpatients.

Severe acute respiratory syndrome coronavirus 2 rapid antigen detection (RAD) test kits are widely used as primary screening test in Japan because rapid diagnosis of coronavirus disease 2019 (COVID-19) is critical for infection control. We report cases with RAD test false-positive results in a ward for patients with disabilities. RAD tests potentially evoke hospital operational risk. It is desirable that performing PCR test appropriately when patients admitted to a medical treatment ward with COVID-19 symptoms instead of RAD test.

Spiral-shaped bacteremia: Difference in the duration of blood cultures between Helicobacter spp. and Campylobacter spp. using the BACTEC system.

Although spiral bacteria are uncommon, they cause bacteremia. We evaluated their characteristics, in particular, the time from the start of blood culture to the first report of a positive result to physicians, using the BACTEC blood culture system. In cases of spiral bacteremia, an extended treatment period should be considered.

Successful Treatment of Breakthrough Trichosporon asahii Fungemia by the Combination Therapy of Fluconazole and Liposomal Amphotericin B in a Patient with Follicular Lymphoma.

Invasive trichosporonosis is a rare and lethal fungal infection that occurs in immunocompromised patients. Breakthrough trichosporonosis can occur in patients treated with echinocandins since Trichosporon spp. are resistant to these antifungal agents. We report a case of breakthrough Trichosporon asahii fungemia. A 62-year-old Japanese woman with relapsed follicular lymphoma was treated empirically with broad-spectrum antibiotics and micafungin due to an intermittent fever during reinduction chemotherapy. After four cycles of anti-cancer chemotherapy, she experienced a high neutropenic fever and T. asahii was subsequently detected from a blood culture. The patient was not given voriconazole due to the contraindication for use with carbamazepine, and she was successfully treated with fluconazole plus liposomal amphotericin B without any serious complications. The combined therapy of fluconazole and liposomal amphotericin B may therefore be useful in treating T. asahii fungemia, especially in patients receiving antiepileptic agents.

The 23-valent pneumococcal polysaccharide vaccine in patients with rheumatoid arthritis: a double-blinded, randomized, placebo-controlled trial.

BACKGROUND: Pneumococcal pneumonia is the most frequent form of pneumonia. We herein assessed the effectiveness of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in the prevention of pneumonia overall in rheumatoid arthritis (RA) patients at risk for infections. We hypothesized that PPSV23 vaccination is superior in preventing pneumococcal pneumonia compared with placebo in RA patients. METHODS: A prospective, multicenter, double-blinded, randomized, placebo-controlled (1:1) trial was conducted across departments of rheumatology in Japanese National Hospital Organization hospitals. RA patients (n = 900) who had been treated with biological or immunosuppressive agents were randomly assigned PPSV23 or placebo (sodium chloride). The primary endpoints were the incidences of all-cause pneumonia and pneumococcal pneumonia. The secondary endpoint was death from pneumococcal pneumonia, all-cause pneumonia, or other causes. Cox regression models were used to estimate the risk of pneumonia overall for the placebo group compared with the vaccine group. RESULTS: Seventeen (3.7%) of 464 patients in the vaccine group and 15 (3.4%) of 436 patients in the placebo group developed pneumonia. There was no difference in the rates of pneumonia between the two study groups. The overall rate of pneumonia was 21.8 per 1000 person-years for patients with RA. The presence of interstitial pneumonia (hazard ratio: 3.601, 95% confidence interval: 1.547-8.380) was associated with an increased risk of pneumonia in RA patients. CONCLUSION: PPSV23 does not prevent against pneumonia overall in RA patients at relative risk for infections. Our results also confirm that the presence of interstitial lung disease is associated with pneumonia in Japanese patients with RA. TRIAL REGISTRATION: UMIN-CTR UMIN000009566 . Registered 17 December 2012.

Neutrophil CD64 level as a rapid and promising diagnostic tool for infectious diseases in elderly patients.

AIM: We examined the utility of the neutrophil CD64 level as a rapid and sensitive diagnostic marker for infections in febrile aged patients. METHODS: The expression level of CD64 per neutrophil was quantitatively measured with flow cytometry using a QuantiBrite kit in samples from febrile (aged >65 years) patients. Information about the presence or absence of infectious disease was retrospectively obtained from each patient's medical record in which attending physicians were obliged to write down a tentative diagnosis after resolution of manifestations. RESULTS: With receiver operating characteristic curve evaluation using the results, a CD64 level >2000 molecules per neutrophil was sensitive and specific for detecting infection. Among 102 patients suspected of having infection, 72 patients were diagnosed with infectious diseases, and 30 patients had non-infectious diseases. The sensitivity and specificity of determination of the neutrophil CD64 level were 88% and 63%, respectively. However, considering the high frequency of infections in elderly patients (71% in the present study), the post-test probability reached as high as 93%. The positive likelihood ratio was 2.4, and the negative likelihood ratio was 0.2. CONCLUSIONS: Considering the frequency of infectious diseases in elderly patients, determination of the neutrophil CD64 level helps detect infectious diseases.

Effect of abatacept on the immunogenicity of 23-valent pneumococcal polysaccharide vaccination (PPSV23) in rheumatoid arthritis patients.

INTRODUCTION: Patients with rheumatoid arthritis (RA) treated with abatacept (ABT) are at increased risk for vaccine-preventable infections. The aim of the present study is to evaluate the humoral response to 23-valent pneumococcal polysaccharide (PPSV23) vaccination in RA patients receiving ABT. METHODS: The immunogenicity study was nested within a randomized, double-blind placebo-controlled study, designed to evaluate the efficacy of the PPSV23. PPSV23 was given to 111 RA patients, who were classified into three groups: RA control (n = 35), methotrexate (MTX) alone (n = 55), and ABT (n = 21). Before and 4-6 weeks after vaccination, we measured the patients' concentrations of antibodies against pneumococcal serotypes 6B and 23F using an enzyme-linked immunosorbent assay and determined their antibody functionality using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI). RESULTS: The pneumococcal serotype-specific IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the ABT group, the IgG responses for the 6B serotype were lower compared with those in the MTX alone or control groups, whereas the OI responses were similar to those in the other two groups. In a subgroup analysis, the pneumococcal serotype-specific IgG responses were significantly lower in both serotypes (6B and 23F) in the ABT/MTX group; however, the OI responses in the ABT group were not different from the control group. There was no association between the pneumococcal serotype-specific IgG and OI responses for the 6B serotype in patients receiving ABT in contrast to the control or MTX alone patients. No severe adverse effects were observed in any of the treatment groups. CONCLUSIONS: OI responses indicate antibody functionality rather than simply their amount, so the similarity of these measurements between all three groups suggests that RA patients receiving ABT still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. The results suggest an influence of ABT on the humoral response to PPSV23 vaccination under MTX treatment; however, preserved opsonin responses are expected in RA patients treated with ABT plus MTX. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.

Opsonic and Antibody Responses to Pneumococcal Polysaccharide in Rheumatoid Arthritis Patients Receiving Golimumab Plus Methotrexate.

Vaccination against Streptococcus pneumoniae is recommended for rheumatoid arthritis (RA) patients receiving immunosuppressive treatments. The objective of this study was to evaluate the humoral response to 23-valent pneumococcal polysaccharide vaccination (PPSV23) in RA patients receiving methotrexate (MTX) alone or in combination with a tumor necrosis factor inhibitor, golimumab (GOM).PPSV23 was given to 114 RA patients, who were classified into three groups: RA control (n = 35), MTX alone (n = 55), and GOM + MTX (n = 24). Before and 4 to 6 weeks after vaccination, concentrations of antibodies against pneumococcal serotypes 6B and 23F were measured using an enzyme-linked immunosorbent assay and antibody functionality was determined using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI).The IgG concentrations and OIs were both significantly increased in all treatment groups in response to PPSV23 vaccination. In the GOM + MTX group, the IgG responses were lower than those in the MTX alone or control groups, whereas the OI responses were similar to those in the other 2 groups. Furthermore, discrepancies between the IgG and OI responses were found in GOM + MTX group. No severe adverse effect was observed in any treatment groups.OI responses indicate that antibody functionality rather than antibody quantity is important. The similarity of these measurements between all 3 groups suggests that RA patients receiving MTX + GOM still benefit from receiving the PPSV23 vaccination, even though they produce less IgG in response to it. These results can help clinicians to better schedule and evaluate pneumococcal vaccination for RA patients.

Pneumococcal polysaccharide vaccination in rheumatoid arthritis patients receiving tacrolimus.

INTRODUCTION: In rheumatoid arthritis (RA) patients receiving immunosuppressive treatments, vaccination against Streptococcus pneumoniae is recommended. The objective of the study was to evaluate the effects of tacrolimus (TAC) on immune response following administration of a 23-valent pneumococcal polysaccharide vaccine (PPSV23) in patients with established RA. METHODS: Patients with RA (n = 133) were vaccinated with PPSV23. Patients were classified into TAC (n = 29), methotrexate (MTX) (n = 55), control (n = 35), and TAC/MTX (n = 14) treatment groups. We measured the concentrations of pneumococcal serotypes 6B and 23F by using an enzyme-linked immunosorbent assay and determined antibody functionality by using a multiplexed opsonophagocytic killing assay, reported as the opsonization index (OI), before and 4 to 6 weeks after vaccination. A positive antibody response was defined as at least a twofold increase in the IgG concentration or as at least a 10-fold increase in the OI. RESULTS: IgG concentrations and OIs were significantly increased in all treatment groups after PPSV23 vaccination. The TAC treatment group appears to respond in a manner similar to that of the RA control group in terms of 6B and 23F serotype concentration and function. In contrast, the MTX group had the lowest immune response. Patients who received a combination of TAC and MTX (TAC/MTX) also had a diminished immune response compared with those who received TAC alone. CONCLUSIONS: TAC monotherapy does not appear to impair PPSV23 immunogenicity in patients with RA, whereas antibody production and function may be reduced when TAC is used with MTX. Thus, PPSV23 administration during ongoing TAC treatment should be encouraged for infection-prone TAC-treated patients with rheumatic diseases. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry: UMIN000009566. Registered 12 December 2012.

Predictors of mortality in patients with interstitial lung disease treated with corticosteroids: results from a cohort study.

Interstitial lung disease (ILD) has a heterogeneous clinical presentation and establishing prognosis for these patients is challenging. We investigated the clinical characteristics and outcome of patients with idiopathic interstitial pneumonias (IIPs) and patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). We conducted a multicenter prospective study on 104 patients diagnosed with IIPs and 29 patients diagnosed with CTD-ILD, which were newly diagnosed and treated with corticosteroids initially. We compared the clinical characteristics, high-resolution computed tomography (HRCT) imaging date, and outcomes. Cox proportional hazard regression analysis was used to identify variables with increased risk of death. Survival was analyzed according to the Kaplan-Meier method and was assessed with the log-rank test. Of 133 patients with IIPs (n = 104) or CTD-ILD (n = 29), 44 patients died during the follow-up period (mean: 1.6 ±â€Š0.78 years). Patients with IIPs seemed to be associated with worse survival compared with those with CTD-ILD; however, this difference was not significant (log-rank test, P = 0.084). Significant predictors for mortality in patients with IIPs at baseline were lower for performance status and definite usual interstitial pattern (UIP) on HRCT. Patients with UIP experienced worse survival than those with non-UIP. A definite UIP on HRCT and lower baseline performance status have important prognostic implications in patients with IIPs.

Rates of serious intracellular infections in autoimmune disease patients receiving initial glucocorticoid therapy.

BACKGROUND/AIMS: The Japanese National Hospital Organization evidence-based medicine (EBM) Study group for Adverse effects of Corticosteroid therapy (J-NHOSAC) is a Japanese hospital-based cohort study investigating the safety of the initial use of glucocorticoids (GCs) in patients with newly diagnosed autoimmune diseases. Using the J-NHOSAC registry, the purpose of this observational study is to analyse the rates, characteristics and associated risk factors of intracellular infections in patients with newly diagnosed autoimmune diseases who were initially treated with GCs. METHODOLOGY/PRINCIPAL FINDINGS: A total 604 patients with newly diagnosed autoimmune diseases treated with GCs were enrolled in this registry between April 2007 and March 2009. Cox proportional-hazards regression was used to determine independent risk factors for serious intracellular infections with covariates including sex, age, co-morbidity, laboratory data, use of immunosuppressants and dose of GCs. Survival was analysed according to the Kaplan-Meier method and was assessed by the log-rank test. There were 127 serious infections, including 43 intracellular infections, during 1105.8 patient-years of follow-up. The 43 serious intracellular infections resulted in 8 deaths. After adjustment for covariates, diabetes (Odds ratio [OR]: 2.5, 95% confidence interval [95% CI] 1.1-5.9), lymphocytopenia (≦1000/µl, OR: 2.5, 95% CI 1.2-5.2) and use of high-dose (≧30 mg/day) GCs (OR: 2.4, 95% CI 1.1-5.3) increased the risk of intracellular infections. Survival curves showed lower intracellular infection-free survival rate in patients with diabetes, lymphocytopaenia and high-dose GCs treatments. CONCLUSIONS/SIGNIFICANCE: Patients with newly diagnosed autoimmune diseases were at high risk of developing intracellular infection during initial treatment with GCs. Our findings provide background data on the risk of intracellular infections of patients with autoimmune diseases. Clinicians showed remain vigilant for intracellular infections in patients with autoimmune diseases who are treated with GCs.