Malnutrition according to the GLIM criteria with kidney dysfunction is associated with increased mortality in hospitalized patients with cardiovascular disease: A retrospective cohort study.

BACKGROUND & AIMS: Cardiovascular disease (CVD) is a significant cause of mortality and rising healthcare costs, involving numerous chronic and nutritional risk. Although several studies have reported that malnutrition based on the Global Leadership Initiative on Malnutrition (GLIM) criteria is associated with mortality in patients with CVD, they have not evaluated this association in terms of malnutrition severity (moderate or severe). Furthermore, the relationship between malnutrition combined with renal dysfunction, a risk factor for death in CVD patients, and mortality has not been previously evaluated. Thus, we aimed to assess the association between malnutrition severity and mortality, as well as malnutrition status stratified by kidney function and mortality, in patients hospitalized due to CVD events. METHODS: This single-centre, retrospective cohort study included 621 patients with CVD aged ≥18 years admitted to Aichi Medical University between 2019 and 2020. The relationship between nutritional status based on the GLIM criteria (without malnutrition, moderate malnutrition, or severe malnutrition) and the incidence of all-cause mortality was evaluated by multivariable Cox proportional hazards models. RESULTS: Patients with moderate and severe malnutrition were significantly more prone to mortality than those without malnutrition (adjusted hazard ratio [HR] of patients without, with moderate, and with severe malnutrition: 1.00 [reference], 1.94 [1.12-3.35], and 2.63 [1.53-4.50], respectively). Furthermore, we found the highest all-cause mortality rate in patients with malnutrition and a lower estimated glomerular filtration rate (eGFR <30 mL/min/1.73 m2) (adjusted HR, 10.1; confidence interval, 3.90-26.4) than in patients without malnutrition and normal eGFR (eGFR ≥60 mL/min/1.73 m2). CONCLUSIONS: The present study indicated that malnutrition according to the GLIM criteria was associated with increased all-cause mortality in patients with CVD, and malnutrition associated with kidney dysfunction was associated with a higher risk of mortality. These findings provide clinically relevant information to identify high mortality risk in patients with CVD and highlight the need for giving careful attention to malnutrition with kidney dysfunction among patients with CVD.

A case of 2,8-DHA crystalline nephropathy caused by adenine phosphoribosyltransferase deficiency: diagnosis and treatment.

Adenine phosphoribosyltransferase (APRT) deficiency is a rare autosomal recessive disorder that leads to the accumulation of poorly soluble 2,8-dihydroxyadenine (DHA) in the kidneys, resulting in a variety of renal presentations including nephrolithiasis, acute kidney injury, and chronic kidney disease (CKD) caused by crystal nephropathy. Here, we report a case of a 43-year-old man with 2,8-DHA crystalline nephropathy caused by APRT deficiency strongly suspected by renal biopsy results and definitively diagnosed by a urine gas chromatography-mass spectrometry (GC/MS)-based plasma metabolomic assessment. This case represents the importance of awareness and recognition of the signs and symptoms of this rare condition and its progression to CKD, which can be prevented by the early administration of xanthine oxidoreductase inhibitors.

Mepolizumab administration for eosinophilic granulomatosis with polyangiitis in an elderly patient with an abrupt onset of limb ischaemia and peripheral neuropathy: A case-based literature review.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of anti-neutrophil cytoplasmic antibody-associated vasculitis characterised by small- to medium-sized vessel vasculitis and is typically associated with eosinophilic granulomatous inflammation. EGPA can affect any organ system, most commonly the lungs, skin, and the nervous system. However, limb ulcers are rare complications and have only been described in few case reports. Furthermore, no documented cases of EGPA have been treated with mepolizumab. Herein, we report a case of an 86-year-old Japanese woman with anti-neutrophil cytoplasmic antibody-negative EGPA, who had an abrupt onset of upper limb ulcers and bilateral foot drop due to multiple mononeuropathy. Clinicopathological sural nerve biopsy showed eosinophil-associated vascular damage. The patient was administered steroids, intravenous immunoglobulin, vasodilators, and mepolizumab; this resulted in clinical improvement of her finger ulcers and peripheral neuropathy without any adverse effects. In cases of an abrupt onset of limb ischaemia and peripheral neuropathy, physicians should consider the possibility of EGPA as a differential diagnosis. Furthermore, the early administration of mepolizumab might yield better outcomes in terms of improving limb ischaemia and peripheral neuropathy.

Association of alcohol consumption with the incidence of proteinuria and chronic kidney disease: a retrospective cohort study in Japan.

BACKGROUND: The difference in the clinical impact of alcohol consumption on kidney function based on sex remains to be elucidated. This study aimed to assess the association between the dose of alcohol consumption and the incidence of proteinuria and chronic kidney disease stratified by sex. METHODS: This retrospective cohort study included 26,788 workers (19,702 men and 7086 women) with normal renal function (estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2) at annual health examinations between January 2010 and March 2015 in Japan. The main exposure was alcohol consumption. The primary outcomes were the incidence of proteinuria (dipstick urinary protein ≥ 1) and incidence of low estimated glomerular filtration rate (eGFR; rate < 60 mL/min per 1.73 m2; decreased from the baseline eGFR by 25%). RESULTS: During a median observational period of 4 years (interquartile range: 2-6), 1993 (10.1%) men and 462 (6.5%) women developed proteinuria, whereas 667 (3.4%) men and 255 (3.6%) women developed low eGFR. After adjustment for clinically relevant factors using a Cox proportional hazards model, alcohol consumption of ≥ 46 g/day in females was significantly associated with the incidence of proteinuria (hazard ratio, 1.57; 95% confidence interval, 1.10-2.26) and low eGFR (hazard ratio, 1.62; 95% confidence interval, 1.04-2.53). However, no significant association between alcohol consumption and primary outcomes was observed in men. CONCLUSIONS: In conclusion, daily higher alcohol consumption was significantly associated with a higher incidence of proteinuria and low eGFR among women. Women might be prone to high alcohol consumption with kidney dysfunction.

Anti-neutrophil cytoplasmic antibody-associated vasculitis complicated by thrombotic microangiopathy with posterior reversible encephalopathy syndrome successfully treated with eculizumab: A case report.

Thrombotic microangiopathy is characterised by endothelial cell injury, intravascular platelet-fibrin thrombi, and vascular damage, leading to acute kidney injury, thrombocytopenia, and microangiopathic haemolytic anaemia. Among the autoimmune diseases related to thrombotic microangiopathy, anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy cases have been rarely reported; therefore, the optimal treatment for associated vasculitis-related thrombotic microangiopathy remains unknown. An 84-year-old woman without significant medical history presented with a 1-month history of general fatigue, fever, and deteriorating bilateral leg numbness and was admitted to our hospital. She had elevated myeloperoxidase anti-neutrophil cytoplasmic antibody levels, polyneuropathy, and rapid progressive glomerulonephritis because of pauci-immune crescentic glomerulonephritis, as revealed by a kidney biopsy. Accordingly, we diagnosed her with microscopic polyangiitis. After administering methylprednisolone pulse therapy, rituximab, and intravenous immunoglobulin, the patient's mental state deteriorated, presenting signs of thrombotic microangiopathy with posterior reversible encephalopathy syndrome. Intermittent haemodialysis and plasma exchange were initiated; however, her condition did not improve, and eculizumab administration was initiated thereafter. The patient's symptoms showed a remarkable response to eculizumab; thrombotic microangiopathy findings, kidney function, and neurological symptoms improved after only two doses of eculizumab, and she achieved sustained remission. The extremely effective course of eculizumab treatment indicated that overt complement activation affected the development of thrombotic microangiopathy. Anti-neutrophil cytoplasmic antibody-associated vasculitis-related thrombotic microangiopathy may be mediated by complement activation, and prompt induction of eculizumab therapy may be a superior strategy to prevent organ damage. Further studies should elucidate the role of complement activation in associated vasculitis-related thrombotic microangiopathy and the efficacy of eculizumab treatment.

Primary cutaneous methotrexate-associated B-cell lymphoproliferative disorders other than EBV-positive mucocutaneous ulcer: clinical, pathological, and immunophenotypic features.

Methotrexate (MTX)-associated B-cell lymphoproliferative disorders (B-LPD) may first present in the skin. Epstein-Barr virus (EBV)-positive mucocutaneous ulcer (EBVMCU) is now a well known disease listed in the 2017 World Health Organization classification. However, primary cutaneous MTX-associated B-LPD (pcMTX B-LPD), other than EBVMCU, appear to be underestimated, and their distinctiveness remains unproven. This study aimed to document the clinicopathological characteristics of nine patients with pcMTX B-LPD that were not EBVMCU to extend our understanding of this peculiar disease. The cohort included three males and six females, with a median age of 74 years (range 54-83 years). All patients were treated with MTX for RA. Of nine patients, four presented with a solitary lesion, and five had multiple lesions. Histologically, five cases showed a polymorphic pattern, and four showed a monomorphic pattern. Immunohistochemically, four cases showed positive EBER staining, and one showed positive CD5 staining. In eight cases, once pcMTX B-LPD was diagnosed, methotrexate was immediately withdrawn. All eight of these patients experienced spontaneous regression and achieved complete remission (CR), without relapse. The patient with CD5 positivity received cytotoxic chemotherapy as the initial treatment. This patient achieved a CR after the initial treatment, but eventually experienced disease relapse resulting in death. We also revealed that pcMTX B-LPD and MTX-associated EBVMCU exhibited similar biological behaviours. We concluded that most pcMTX B-LPD cases could be cured by stopping MTX treatment. We also highlighted the fact that pcMTX B-LPD and MTX-EBVMCU had overlapping features. This finding suggested that pcMTX B-LPD and MTX-EBVMCU might share an underlying mechanism.

Association between sinusitis and relapse and changes in the myeloperoxidase-antineutrophil cytoplasmic antibody in microscopic polyangiitis.

Previous studies have evaluated the risk factors for relapse of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and the biomarkers of AAV for predicting relapse. However, little is known about the association between the presence of sinusitis and relapse and changes in the ANCA levels in AAV. This single-center, retrospective cohort study included 104 consecutive patients who were newly diagnosed with myeloperoxidase (MPO)-ANCA-positive microscopic polyangiitis (MPA) between 2006 and 2018 and were treated at the Aichi Medical University Hospital in Japan. The relationships between sinusitis and relapse of vasculitis and elevated MPO-ANCA levels were assessed using multivariate Cox proportional hazards models that were adjusted for clinically relevant factors. During the entire follow-up period (median, 24 months; interquartile range, 7-54 months), 93 (89.4%) patients achieved remission. After achieving remission, 38 (40.9%) patients experienced at least one relapse (13 [65.0%] in the sinusitis group; 25 [34.3%] in the non-sinusitis group). Sinusitis was identified as a significant predictor of relapse (adjusted hazard ratio: 2.41, 95% confidence interval [CI]: 1.19-4.88; P = 0.015). Furthermore, sinusitis was more likely to be associated with elevated MPO-ANCA levels (adjusted hazard ratio: 2.59, 95% CI: 1.14-5.92; P = 0.024). In conclusion, sinusitis was associated with a higher risk of relapse and elevated MPO-ANCA levels in MPA patients, suggesting that careful management may be required to reduce the risk of relapse in patients with sinusitis. Further studies are needed to elucidate the optimal treatment strategy for these patients.

Successful cessation of tumor necrosis factor inhibitor treatment in rheumatoid arthritis patients and potential predictors for early flare: An observational study in routine clinical care.

Objectives: To investigate the prevalence and the consequence of tumor necrosis factor inhibitor (TNFi) cessation after clinical improvement in rheumatoid arthritis (RA) patients in clinical practice and predictors of flare after TNFi cessation.Methods: We retrospectively assessed the prevalence of TNFi cessation after achieving sustained improvement, disease flare and joint damage progression after TNFi cessation in consecutive RA patients who started TNFi due to insufficient response to methotrexate were studied. Predictors for flare after TNFi cessation were investigated using Cox regression analysis.Results: In 135 patients who started TNFi with methotrexate, 95 stopped TNFi after sustained improvement and continued methotrexate thereafter. Over 1 year, 33 patients had a flare and 26 restarted TNFi therapy. In 78 patients whose radiographs adequate for evaluation were available, 73 did not exhibit joint damage progression. Female gender, smoking, the interval from starting methotrexate to starting TNFi of more than 9 months and glucocorticoid use at starting TNFi were independently associated with shorter time to flare.Conclusion: Sixty-five percent of patients were successfully discontinued TNFi over 1 year. Radiographic joint damage progression was rare. Early intervention with TNF inhibitor may contribute to successful TNF inhibitor cessation in patients with insufficient response to methotrexate.Key messageSuccessful TNF inhibitor cessation is achievable in two-third of RA patients after achieving sustained remission.Female gender and smoking may predispose to flare after TNF inhibitor cessation.Early intervention with TNF inhibitor may contribute to successful TNF inhibitor cessation.

Carboplatin-related acute interstitial nephritis in a patient with pancreatic neuroendocrine tumor.

Carboplatin is characterized by low nephrotoxicity, including acute tubular necrosis (ATN), compared to a conventional platinum complex due to its low accumulative property in the renal tubules. Therefore, there are extremely few reports of carboplatin-induced kidney injury and only one case has been histologically examined. Herein, we describe the case of a 53-year-old man who presented with acute kidney injury (AKI) that occurred after carboplatin administration and was diagnosed with biopsy-proven acute interstitial nephritis (AIN). To our knowledge, this is the second case report of carboplatin-related AIN. The patient was diagnosed with a pancreatic neuroendocrine tumor, and chemotherapy consisting of cisplatin and irinotecan was initiated. However, 1 week later, he was admitted to our institution with fever, fatigue and an increase in C-reactive protein (CRP) level. The chemotherapy regimen was altered to carboplatin and etoposide, but high fever occurred on the first day, and CRP re-elevation and AKI became apparent 9 days later. Renal biopsy revealed prominent inflammatory cell infiltration into the interstitium, which lead to the pathological diagnosis of AIN. On immunostaining for surface markers, CD3- and CD68-positive cells were found to be predominant, and CD20-positive cells were relatively few. Although the serum creatinine level increased to 6.81 mg/dL, it decreased to 1.43 mg/dL 15 days after steroid therapy. This case demonstrated that carboplatin-related kidney injury includes not only ATN but also AIN. Appropriate pathological diagnosis including renal biopsy and indications for steroid treatment should be carefully considered.

Long-term efficacy and safety of add-on tacrolimus for persistent, active rheumatoid arthritis despite treatment with methotrexate and tumor necrosis factor inhibitors.

AIM: To assess the long-term efficacy and safety of adding tacrolimus for patients with active rheumatoid arthritis (RA) despite anti-tumor necrosis factor (TNF) therapy with methotrexate. METHODS: Consecutive patients who were treated with adding tacrolimus onto anti-TNF therapy with methotrexate for active RA despite anti-TNF therapy with methotrexate, were retrospectively analyzed in terms of treatment response, achieving remission, subsequent treatment tapering and adverse events. RESULTS: Fifteen patients could be analyzed. Median symptom duration was 2.9 years and prior duration of anti-TNF therapy was 40 weeks. Median value of Disease Activity Score in 28 joints was 4.6. Five, eight and two were on infliximab, etanercept and adalimumab at the onset of tacrolimus, respectively. At 2 years, the proportions of patients achieving responses of American College of Rheumatology 50, 70 and 90, were 80%, 73% and 40%, respectively, and those achieving remission as defined by Simplified Disease Activity Index ≤ 3.3 were 67%. All patients could discontinue oral glucocorticoids and 10 had been successfully withdrawn from anti-TNF therapy for more than 1 year at the final observation. CONCLUSION: Adding tacrolimus onto anti-TNF therapy is a promising therapeutic option with sustained benefit for refractory RA patients despite treatment with anti-TNF therapy combined with methotrexate.

Improvement of Arterial Wall Lesions in Parallel with Decrease of Plasma Pentraxin-3 Levels in a Patient with Refractory Takayasu Arteritis after Treatment with Tocilizumab.

A 19-year-old Japanese woman with active Takayasu arteritis despite multiple conventional immunosuppressive therapies with glucocorticoids in combination with intravenous cyclophosphamide, azathioprine, or infliximab with methotrexate and tacrolimus was successfully treated by switching from infliximab to intravenous tocilizumab. Worsening of claudication of the legs and elevated acute phase reactants, including plasma pentraxin-3 levels, were observed during combination therapy with infliximab. Computed tomography demonstrated increased wall thickening with contrast enhancement in the preexisting lesion of the descending aorta and the femoral arteries. After switching from infliximab to tocilizumab, plasma pentraxin-3 levels gradually decreased to the normal range in parallel with the improvement of claudication. Follow-up computed tomographic scans confirmed the marked improvement of these arterial lesions. Moreover, plasma pentraxin-3 level was increased in response to the worsening of claudication that occurred just after switching to a subcutaneous tocilizumab injection. Measurements of plasma pentraxin-3 might be useful for evaluation of the vascular wall inflammation and therapeutic efficacy even during biologic therapy targeting tumor necrosis factor α and interleukin-6.

Efficacy of add-on tacrolimus on methotrexate to maintain clinical remission after rediscontinuation of a tumor necrosis factor inhibitor in rheumatoid arthritis patients who relapsed shortly after discontinuation of the same tumor necrosis factor inhibitor due to clinical remission.

OBJECTIVES: To describe the efficacy of adding tacrolimus to maintain remission in patients with rheumatoid arthritis (RA) on methotrexate after discontinuation of tumor necrosis factor inhibitor (TNFi) therapy. METHODS: Consecutive patients with RA, who resumed a TNFi to treat flares after initial TNFi-free remission and discontinued a TNFi again after achieving remission and adding tacrolimus were enrolled. The lengths of remission after discontinuation of TNFi without or with tacrolimus were analyzed. RESULTS: Thirteen TNFi-free periods in six patients, in which seven were without and six were with tacrolimus were analyzed. All were seropositive females with a median age of 46 years and symptom duration of 1.2 years at the onset of TNFi therapy. Two were treated with infliximab and four were with etanercept. The median dose of tacrolimus was 2 mg/day with trough level of 4.5 ng/ml. The length of time to flare after discontinuation of TNFi therapy with tacrolimus was significantly longer than those without tacrolimus (median 107 weeks [range 4-207] versus 13 weeks [2-36]). After adding tacrolimus, only one patient resumed TNFi therapy and three had no flare until final observation. CONCLUSIONS: Add-on tacrolimus was effective in maintaining TNFi-free remission in patients with RA who ever relapsed after TNFi-free remission.

Successful Use of Higher-Dose Etanercept for Multirefractory Systemic Flare of Adult-Onset Still's Disease with Liver Failure with No Response to Tocilizumab Therapy.

A 21-year-old woman with refractory systemic flare of adult-onset Still's disease with liver failure despite high-dose corticosteroids, cyclosporine, tacrolimus, and tocilizumab, was successfully treated with additional use of etanercept. Etanercept at a dose of 50 mg weekly was partially effective but could not reduce the dose of concomitant betamethasone from 5 mg/day. Etanercept at a dose of 75 mg weekly could lead her to clinical remission and enabled successful tapering off the corticosteroids and discontinuation of etanercept. Normalization of serum C-reactive protein and interleukin 6 and persistent elevation of serum tumor necrosis factor α under the treatment with high-dose corticosteroids and immunosuppressants suggest that tumor necrosis factor α was more deeply involved than at least interleukin 6 in the pathogenesis of refractoriness of the disease in this patient, and these findings might be indicative of potential efficacy for adjunctive use of a tumor necrosis factor inhibitor rather than an interleukin 6 inhibitor.