Renal Immune-related Adverse Event of Pembrolizumab Masked by Pemetrexed.

A Japanese woman in her 60s developed a kidney injury 9 weeks after treatment with pemetrexed, carboplatin, and pembrolizumab for stage IV lung adenocarcinoma. A renal biopsy showed chronic tubulointerstitial damage with minimal focal interstitial inflammation, consistent with pemetrexed-induced nephropathy; thus, pemetrexed was withdrawn. However, the kidney injury continued to worsen. A repeated biopsy showed severe acute tubulointerstitial nephritis, suggestive of a pembrolizumab-induced immune-related adverse event (irAE). The worsening after pemetrexed discontinuation suggested that the irAE had already begun, as the first biopsy showed focal inflammation. This case suggests thatcombining immune checkpoints and chemotherapy requires considering concurrent drug-induced nephrotoxicity.

Predictive correction of serum sodium concentration with formulas derived from the Edelman equation in patients with severe hyponatremia.

Severe hyponatremia can cause life-threatening cerebral edema. Treatment comprises rapid elevation of serum sodium concentration; however, overcorrection can result in osmotic demyelination. This study investigated potential factors, including predictive correction based on the Edelman equation, associated with appropriate correction in 221 patients with a serum sodium concentration ≤ 120 mEq/L who were admitted to a hospital in Nagoya, Japan. Appropriate correction was defined as an elevation in serum sodium concentration in the range of 4-10 mEq/L in the first 24 h and within 18 mEq/L in the first 48 h after the start of the correction. Appropriate corrections were made in 132 (59.7%) of the 221 patients. Multivariate analysis revealed that predictive correction with an infusate and fluid loss formula derived from the Edelman equation was associated with appropriate correction of serum sodium concentration (adjusted odds ratio, 7.84; 95% confidence interval, 2.97-20.64). Relative without its use, the predictive equation results in a lower proportion of undercorrection (14.3% vs. 48.0%, respectively) and overcorrection (1.0% vs. 12.2%, respectively). These results suggest that predictive correction of serum sodium concentrations using the formula derived from the Edelman equation can play an essential role in the appropriate management of patients with severe hyponatremia.

Application of MALDI-TOF MS to assess clinical characteristics, risk factors, and outcomes associated with anaerobic bloodstream infection: a retrospective observational study.

BACKGROUND: Correctly identifying anaerobic bloodstream infections (BSIs) is difficult. However, a new technique, matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), enables more accurate identification and appropriate treatment. Anaerobic BSIs identified by MALDI-TOF MS were retrospectively analyzed to determine the clinical and microbiological features and patient outcomes based on the anaerobic genera or group. METHODS: Medical records of patients with anaerobic BSIs were used to conduct a single-center retrospective cohort study from January 2016 to December 2020 in Nagoya, Japan. Multivariate logistic regression analysis was performed to determine the independent risk factors for in-hospital mortality. RESULTS: Of the 215 patients with anaerobic BSIs, 31 had multiple anaerobic organisms in the blood culture, including 264 total episodes of anaerobic BSIs. Bacteroides spp. were isolated the most (n = 74), followed by gram-positive non-spore-forming bacilli (n = 57), Clostridium spp. (n = 52), gram-positive anaerobic cocci (GPAC) (n = 27), and gram-negative cocci (n = 7). The median patient age was 76 years; 56.7% were male. The most common focal infection site was intra-abdominal (36.7%). The in-hospital mortality caused by anaerobic BSIs was 21.3%, and was highest with Clostridium spp. (36.5%) and lowest with GPAC (3.7%). Age, solid tumors, and Clostridium spp. were independent risk factors for in-hospital mortality. CONCLUSIONS: We identified current anaerobic BSI trends using MALDI-TOF MS and reported that mortality in patients with anaerobic BSIs patients was highest with Clostridium spp. infections.

Combined light chain crystalline tubulopathy, podocytopathy, and histiocytosis associated with Bence-Jones κ protein diagnosed via immuno-electron microscopy.

We herein report a case of a combined crystalline light chain tubulopathy, podocytopathy, histiocytosis, and cast nephropathy in a patient with monoclonal gammopathy of renal significance (MGRS). A 66-year-old female with impaired renal function was referred to our department. Despite intravenous fluid resuscitation, the kidney function worsened progressively; thus, a kidney biopsy was performed. The kidney biopsy revealed light chain proximal tubulopathy (LCPT) with crystals, light chain crystal podocytopathy (LCCP), crystal-storing histiocytosis (CSH), and light chain cast nephropathy (LCCN). Of note, LCCP and CSH were diagnosed via electron microscopy. Serum and urine immunoelectrophoresis (IEP) revealed the presence of monoclonal Bence-Jones protein and free κ light chains. Bone marrow aspiration showed < 10% plasma cell proliferation. Thus, we had encountered a rare case in which a variety of kidney lesions were combined with MGRS. Most of the LCPT, LCCP, and CSH cases show monoclonal IgG κ, while our case showed Bence-Jones protein κ.

An open-label, randomized controlled trial of sulfamethoxazole-trimethoprim for Pneumocystis prophylaxis: results of 52-week follow-up.

OBJECTIVES: The aim was to investigate the long-term prophylactic efficacy, drug retention and safety of low-dose sulfamethoxazole-trimethoprim (SMX/TMP) prophylaxis against Pneumocystis pneumonia (PCP). METHODS: Adult patients with rheumatic diseases receiving prednisolone ≥0.6 mg/kg/day were randomized into the single-strength group (SS; SMX/TMP 400/80 mg daily), the half-strength group (HS; 200/40 mg daily) or the escalation group (ES; starting at 40/8 mg and increasing incrementally to 200/40 mg daily) and treated for 24 weeks, then observed for 52 weeks. The primary endpoint, the PCP non-incidence rate (non-IR) at week 24, has been reported previously. The secondary endpoints were the PCP non-IR at week 52, treatment discontinuation rate and adverse events. RESULTS: Fifty-eight, 59 and 55 patients in the SS, HS and ES, respectively, received SMX/TMP. PCP did not develop in any of the patients by week 52. The estimated PCP non-IR in patients receiving SMX/TMP 200/40 mg daily (HS and ES) was 96.8-100%. Throughout the 52-week observation period, the overall discontinuation rate was significantly lower in HS than in SS (22.7 vs 47.2%, P = 0.004). The discontinuation rates attributable to adverse events were significantly lower in HS (19.1%, P = 0.007) and ES (20.3%, P = 0.007) than in SS (41.8%). The IRs of adverse events requiring SMX/TMP dose reduction before week 52 differed among the three groups, with a significantly higher IR in SS than in HS or ES (P = 0.007). CONCLUSION: SMX/TMP 200/40 mg had a high PCP prevention rate and was superior to SMX/TMP 400/80 mg in terms of drug retention and safety. TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry, UMIN000007727.

Identification of molecules associated with response to abatacept in patients with rheumatoid arthritis.

BACKGROUND: Abatacept (ABA) is a biological disease-modifying antirheumatic drug (bDMARD) for rheumatoid arthritis (RA). The aim of this study was to identify molecules that are associated with therapeutic responses to ABA in patients with RA. METHODS: Peripheral blood was collected using a PAX gene Blood RNA kit from 45 bDMARD-naïve patients with RA at baseline and at 6 months after the initiation of ABA treatment. Gene expression levels of responders (n = 27) and non-responders (n = 8) to ABA treatment among patients with RA at baseline were compared using a microarray. The gene expression levels were confirmed using real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: Gene expression analysis revealed that the expression levels of 218 genes were significantly higher and those of 392 genes were significantly lower in the responders compared to the non-responders. Gene ontology analysis of the 218 genes identified "response to type I interferon (IFN)" with 24 type I IFN-related genes. RT-qPCR confirmed that there was a strong correlation between the score calculated using the 24 genes and that using OAS3, MX1, and IFIT3 (type I IFN score) (rho with the type I IFN score 0.981); the type I IFN score was significantly decreased after treatment with ABA in the responders (p < 0.05), but not in the non-responders. The receiver operating characteristic curve analysis of the type I IFN score showed that sensitivity, specificity, and AUC (95% confidence interval) for the responders were 0.82, 1.00, and 0.92 (0.82-1.00), respectively. Further, RT-qPCR demonstrated higher expression levels of BATF2, LAMP3, CD83, CLEC4A, IDO1, IRF7, STAT1, STAT2, and TNFSF10 in the responders, all of which are dendritic cell-related genes or type I IFN-related genes with significant biological implications. CONCLUSION: Type I IFN score and expression levels of the nine genes may serve as novel biomarkers associated with a clinical response to ABA in patients with RA.

Fatal and extensive multiorgan hemorrhages in anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis: An autopsy case report.

INTRODUCTION: Anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab) is an autoantigen associated with dermatomyositis (DM). Anti-MDA5 Ab-positive DM patients frequently exhibit clinically amyopathic dermatomyositis (CADM), and develop rapidly progressive interstitial lung disease (RPILD). Even with early detection and potent combination immunosuppressive therapy, anti-MDA5 Ab-positive DM patients have a poor prognosis. In the present case report, we present a rare autopsy case of a patient with anti-MDA5 Ab DM with RPILD who exhibited diffuse alveolar damage (DAD) patterning in lung specimens, and extensive hemorrhages in multiple organs. PATIENT CONCERNS: An 82-year-old Japanese man admitted with bacterial pneumonia was subsequently diagnosed with anti-MDA5 Ab-positive DM based on skin manifestations (mechanic's hand, ulcerated palmar papules, and flagellate erythema), myositis, interstitial pneumonia, and elevation of anti-MDA5 Ab titer. DIAGNOSIS: The patient was diagnosed with anti-MDA5 Ab DM, complicated with RPILD. INTERVENTIONS: The patient received potent immunosuppressive therapy consisting of pulse methylpredonisolone at a dose of 1000 mg for 3 days, followed by prednisolone at 60 mg/d, a 1000 mg pulse of intravenous cyclophosphamide (IVCY), and oral tacrolimus at 6 mg/d. Intravenous immunoglobulin (IVIG) at a dose of 400 mg/kg/d for 5 days was subsequently administered. OUTCOMES: Despite triple immunosuppressive therapy and IVIG, the patients' respiratory status deteriorated, and the patient died of respiratory failure on the twelfth day after admission. An autopsy revealed pulmonary DAD and multiorgan hemorrhages, including the left iliopsoas muscle, gastric and bowl mucosa, spleen, and left adrenal gland. LESSONS: Multiorgan hemorrhages may be a fatal complication in anti-MDA5 Ab DM patients.

Comparison of fluorescence optical imaging, ultrasonography and clinical examination with magnetic resonance imaging as a reference in active rheumatoid arthritis patients.

BACKGROUND: Fluorescence optical imaging with indocyanine-green enhancement (FOI) is a new imaging modality for the assessment of hand arthritis. The objective of this study was to compare performance profiles of clinical examination (CE), US and FOI using MRI as a reference in the same active rheumatoid arthritis (RA) patients. METHODS: CE, US, FOI and MRI were performed on six subjects with active RA. Each sequence of FOI was divided into three phases based on indocyanine-green dynamics and the joints were graded semi-quantitatively. Sensitivities and specificities of CE, US and FOI were calculated using the RAMRIS synovitis score >0 as a reference in a total of 30 joints (the second to fifth metacarpophalangeal (MCP) joints and the wrist of the clinically dominant hand). RESULTS: FOI showed sensitivities and specificities, respectively, of 85% and of 94% for Phase-1 and 69% and 94% for Phase-2. Sensitivities and specificities were 100% and 35% for CE (tender or swollen), 92% and 41% for gray scale US, and 77% and 100% for color-Doppler US. CONCLUSIONS: The performance characteristics of FOI in detection of synovitis in patients with active RA are comparable to those of US and more specific than CE. FOI has a potential as an assessment modality of RA.