Systematic review and meta-analysis for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis.

OBJECTIVES: The aim of this article is to update evidence on the efficacy and safety of disease-modifying antirheumatic drugs (DMARDs) and provide information to the taskforce for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for the management of rheumatoid arthritis (RA). METHODS: We searched various databases for randomised controlled trials on RA published until June 2022, with no language restriction. For each of the 15 clinical questions, two independent reviewers screened the articles, evaluated the core outcomes, and performed meta-analyses. RESULTS: Subcutaneous injection of methotrexate (MTX) showed similar efficacy to oral MTX in MTX-naïve RA patients. Ozoralizumab combined with MTX improved drug efficacy compared to the placebo in RA patients with inadequate response (IR) to conventional synthetic DMARD (csDMARD). Rituximab with and without concomitant csDMARDs showed similar efficacy to other biological DMARDs (bDMARDs) in bDMARD-IR RA patients. Combined Janus kinase inhibitors and MTX achieved similar clinical responses and equal safety during a 4-year period compared to tumour necrosis factor inhibitors in MTX-IR RA patients. Biosimilars showed efficacy equivalent to that of the original bDMARDs in csDMARD-IR and bDMARD-IR RA patients. CONCLUSIONS: This systematic review provides latest evidence for the 2024 update of the Japan College of Rheumatology clinical practice guidelines for RA management.

Concomitant pleuritis and pericarditis developing during glucocorticoid therapy: a case report on granulomatosis with polyangiitis.

Granulomatosis with polyangiitis is an anti-neutrophil cytoplasmic antibody-associated vasculitis that manifests in various ways by affecting the small-sized vessels in multiple organs. Acute pleuritis and pericarditis are both rare among the different manifestations of granulomatosis with polyangiitis. The symptoms in each of the organs are often apparent at the time of diagnosis and tend to diminish with treatment. Organ damage and progression of the disease during treatment are uncommon. We encountered a patient with granulomatosis with polyangiitis who, after starting intravenous methylprednisolone pulse therapy, concurrently developed acute pleuritis and pericarditis. The patient was a 47-year-old Japanese man with myalgia in whom kidney dysfunction, proteinase 3-anti-neutrophil cytoplasmic antibody positivity, and a lung mass were detected. Granulomatosis with polyangiitis was diagnosed pathologically from a lung and a kidney biopsy. Acute pleuritis and pericarditis, which developed after the first course of intravenous methylprednisolone pulse therapy, both resolved following the second course. The present report indicates that secondary serositis such as pleuritis and pericarditis can develop in patients with granulomatosis with polyangiitis even during glucocorticoid therapy.

Polyclonal immunoglobulin G deposition on the tubular basement membrane in a diabetic nephropathy: A case report.

A 70-year-old Japanese man with diabetes mellitus was referred to our hospital for treatment of renal dysfunction. Renal biopsy revealed that the tubular basement membrane (TBM) showed extreme thickening histologically, and selective polyclonal immunoglobulin G deposition on the thickened TBM, whereas no immunoglobulin deposition was found in the glomeruli in an immunofluorescence study. In electron microscopy, a powdery type of electron dense material, which was similar to that seen in Randall-type monoclonal immunoglobulin deposition disease (MIDD), was observed on the tubular epithelial side of the TBM. However, the present case was differentiated from MIDD, because polyclonal deposition with both kappa and lambda deposition on the TBM was observed. Moreover, there was no noticeable glomerular deposition, which is usually found in cases of MIDD. Anti-TBM disease was also considered as a differential diagnosis, in which polyclonal immunoglobulin deposits selectively on the TBM. However, in the present case, prominent interstitial nephritis was not observed. A similar case with a history of diabetes mellitus has been reported, which was diagnosed as Polyclonal Immunoglobulin G Deposition Disease. No further reports of this case have emerged thereafter; we present this case as the second report supporting this article.

Rapidly progressive renal failure due to tubulointerstitial infiltration of peripheral T-cell lymphoma, not otherwise specified accompanied by uveitis: a case report.

BACKGROUND: Rapid decline in renal dysfunction due to primary renal lymphoma, or secondary renal lymphoma by infiltration from a primary origin, is extremely rare. There are notably few reports indicating infiltration of T-cell lymphoma into the kidney. CASE PRESENTATION: A 61-year-old woman with a sudden body rash and liver dysfunction was brought to our hospital presenting with a dull headache and blurred vision. Laboratory tests revealed rapidly progressive renal failure. Histological examination of the kidney and skin indicated infiltration of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Infiltration of PTCL-NOS to the liver and spleen, and presence of Uveitis masquerade syndrome were suspected. Imaging showed that the lesion was limited to extralymphatic organs. Renal function was improved with administration of steroids, including pulse steroid therapy, before administering cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) therapy. CONCLUSIONS: This is the first reported case of rapidly progressive renal failure caused by perivascular tubulointerstitial nephritis with the direct invasion of PTCL-NOS. In our case, a single steroid dose showed dramatic results with respect to renal symptoms.

Renovascular hypertension associated with JAK2 V617F positive myeloproliferative neoplasms treated with angioplasty: 2 cases and literature review.

Myeloproliferative neoplasms (MPNs) with Janus kinase 2 (JAK2) mutation are associated with a high risk for occlusive vascular diseases. We report 2 cases of renovascular hypertension associated with JAK2 V617F mutation-positive MPNs and provide a literature review. In Case 1, a 63-year-old woman had resistant hypertension, massive proteinuria, and erythrocytosis. Evaluations revealed right renal artery stenosis causing renovascular hypertension and polycythemia vera with JAK2 V617F mutation. Renin-angiotensin system inhibitors and subsequent angioplasty controlled the blood pressure and the proteinuria resolved. In Case 2, a 74-year-old woman had resistant hypertension and thrombocytosis. Evaluations confirmed left renal artery stenosis and essential thrombocythemia with JAK2 V617F. Angioplasty cured the hypertension. A literature review of 18 cases revealed the following as the most common characteristics of MPN-associated renovascular hypertension: manifests primarily in women; is associated with untreated polycythemia vera and essential thrombocythemia, concomitant leukocytosis, and JAK2 mutation positivity; and is responsive to angioplasty. This report demonstrates that JAK2 mutation-positive MPNs are a less common but important underlying cause of adult renovascular hypertension.

Manual compression and reflex syncope in native renal biopsy.

BACKGROUND: Complications associated with diagnostic native percutaneous renal biopsy (PRB) must be minimized. While life threatening major complications has been extensively investigated, there is little discussion regarding minor bleeding complications, such as a transient hypotension, which directly affect patients' quality of life. There is also little evidence supporting the need for conventional manual compression following PRB. Therefore, this study evaluated the relationship between minor and major complications incidence in patients following PRB with or without compression. METHODS: This single-center, retrospective study included 456 patients (compression group: n = 71; observation group: n = 385). The compression group completed 15 min of manual compression and 4 h of subsequent strict bed rest with abdominal bandage. The observation group completed 2 h of strict bed rest only. The primary outcome of interest was transient symptomatic hypotension (minor event). RESULTS: Of the 456 patients, 26 patients encountered intraoperative and postoperative transient hypotension, which were considered reflex syncope without tachycardia. Univariate analysis showed that symptomatic transient hypotension was significantly associated with compression. This association remained significant, even after adjustment of covariates using multivariate logistic regression analysis (adjusted odds ratio 3.27; 95% confidential interval 1.36-7.82; P = 0.0078). CONCLUSION: Manual compression and abdominal bandage significantly increased the frequency of reflex syncope during native PRB. It is necessary to consider the potential benefit and risk of compression maneuvers for each patient undergoing this procedure.

Anti-neutrophil Cytoplasmic Antibody-associated Vasculitis (AAV) Restricted to the Limbs.

A previously healthy 58-year-old man was admitted for muscle pain and weakness [manual muscle testing (MMT) of 4/4 for upper and lower limbs]. We detected elevated levels of inflammatory makers and PR3-anti-neutrophil cytoplasmic antibody (ANCA). Subsequently, the muscle weakness rapidly progressed to an MMT of 2 for all limbs. Magnetic resonance imaging indicated muscle edema, and the creatine kinase (CK) level increased to 29,998 U/L. Methylprednisolone (mPSL) and cyclophosphamide pulse therapy improved the patient symptoms. MMT recovered to 4 for all limbs. A muscle biopsy showed degenerated muscle fibers surrounded by neutrophil-predominant infiltration. In addition, lamina elastic breakdown and fibrinoid necrosis of arterioles were observed. A final diagnosis of microscopic polyangiitis (MPA) limited to the muscles was made.

Unexpected delayed bleeding after native renal biopsy: a case report.

Percutaneous native renal biopsy is recognized as a safe procedure. The majority of bleeding events occur within 24 h after the procedure, and reports of delayed major complications are very limited. We report a patient presenting with sudden flank pain 7 days after renal biopsy, in whom abdominal computed tomography showed increased hematoma size with extravasation and who was treated with radiological intervention. Careful attention should be paid to diagnose and treat delayed major complications in patients undergoing native renal biopsy.

Quantification of bleeding volume using computed tomography and clinical complications after percutaneous renal biopsy.

Background: The aim of this study was to investigate specific bleeding volume after percutaneous renal biopsy (PRB) and the correlation between bleeding volume and clinical parameters. Methods: A retrospective study of 252 consecutive patients (153 male patients and 99 female patients) who underwent PRB at the Department of Nephrology, Japanese Red Cross Ishinomaki Hospital, between July 2013 and January 2016 was conducted. PRB was performed under ultrasound guidance using an automated spring-loaded biopsy device and a 16-cm, 16-gauge needle. Patients underwent computed tomography (CT) the day after PRB. Bleeding volume after PRB was evaluated using reconstructed CT data. Results: The median bleeding volume after PRB was 38 mL (25th-75th percentile, 18-85 mL), with ≥4 punctures identified as a risk factor for massive bleeding. The incidence rates of macrohematuria, transient hypotension and bladder obstruction were 14.3, 8.7 and 4.7%, respectively. Post-PRB blood transfusion and intervention were required in 4.7 and 0.8% of patients, respectively. Conclusion: Although it is difficult to assess the risk for massive bleeding prior to PRB, we do provide evidence of a specific increased risk with ≥4 puncture attempts, and recommend careful follow-up of these patients.

Perirenal fat stranding is not a powerful diagnostic tool for acute pyelonephritis.

PURPOSE: Pyelonephritis, an upper urinary tract infection, is a serious infection that often requires hospitalization. However, the accurate diagnosis of acute pyelonephritis can be difficult, especially among older individuals who can present with unusual symptoms. Imaging with computed tomography (CT) is not unusual in the diagnosis of pyelonephritis, with some clinicians regarding perirenal fat stranding (PFS) as a characteristic finding. However, the sensitivity and specificity of PFS in diagnosing pyelonephritis are currently unknown. We therefore sought to clarify the relevance of PFS in diagnosing acute pyelonephritis. PATIENTS AND METHODS: We conducted a case-controlled retrospective analysis of medical records. The pyelonephritis group included 89 patients who had been diagnosed with acute pyelonephritis, while the control group included 319 patients who had undergone percutaneous renal biopsy. CT findings were available for both groups. The frequency of PFS and its sensitivity and specificity for the diagnosis of acute pyelonephritis were investigated. RESULTS: The mean ages of the pyelonephritis and control groups were 74±15 years and 63±16 years, respectively. A total of 28% of men were in the pyelonephritis group vs 61% of men in the control group. The frequency of PFS was 72% in the pyelonephritis group vs 39% in the control group. Age and renal dysfunction were associated with an increased frequency of PFS. After adjusting for age, sex, and renal function using a propensity score analysis, the sensitivity, specificity, and positive likelihood ratio of PFS for diagnosing acute pyelonephritis were 72%, 58%, and 1.7, respectively. CONCLUSION: The presence of PFS was not useful in diagnosing acute pyelonephritis.

Remission Induction Therapy with Rituximab for Microscopic Polyangiitis: A Feasibility Study.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is systemic vascular inflammation. Microscopic polyangiitis (MPA) is a major type of AAV in Japan. MPA often affects the kidneys and lungs, leading to death if untreated. Induction therapy (i.e., initial treatment) for MPA has not been optimized, although methylprednisolone and cyclophosphamide are commonly used. Recently, rituximab (RTX) (a monoclonal antibody against the protein CD20) has also been used to treat refractory AAV. RTX at 375 mg/m2/week for 4 weeks (i.e., the conventional lymphoma dosing schedule) is used, but the optimal dosing schedule is controversial. Indeed, a single-dose of RTX successfully controlled nephrotic syndrome. However, to date, the effectiveness of a single RTX dose in treating MPA has not been fully investigated in Japan. This was a retrospective observational study. Six newly diagnosed patients with MPA were initially treated with methylprednisolone and a single dose of RTX (375 mg/m2). We investigated the patients' clinical features, as well as the efficacy and safety of RTX treatment. All patients attained remission on a tapered prednisolone dose of < 10 mg/day during the first 12 months. One patient relapsed after 12 months whereas another required hospitalization owing to infective spondyloarthritis. Adverse reactions to RTX infusion and late-onset neutropenia were not observed. Therefore, a single-dose treatment with RTX induced remission with few complications, and allowed tapering the prednisolone treatment. We conclude that a single dose of RTX is a promising induction therapy for MPA, reducing the cost associated with multiple doses.

IgG4-Related Disease Manifesting as Interstitial Nephritis Accompanied by Hypophysitis.

BACKGROUND IgG4-related disease is a systemic disease with marked infiltration of IgG4-positive plasma cells into affected organs and elevated serum IgG4. On clinical examination, swelling, nodules, and hypertrophic lesions might appear simultaneously or metachronously in different organs. CASE REPORT An 85-year-old man with sudden-onset polydipsia and polyuria insipidus was transported to our hospital because of hypothermia and general malaise. Laboratory tests revealed renal failure and central diabetes insipidus. According to his serum IgG4 level, the patient was diagnosed with possible IgG4-related kidney disease accompanied by IgG4-related hypophysitis. Abdominal contrast-enhanced computed tomography, hypophysis magnetic resonance imaging, and histological examination of the kidney were performed. Glucocorticoid therapy was administered and his renal function improved gradually. However, his central diabetes insipidus did not improve. CONCLUSIONS Glucocorticoid therapy showed different therapeutic effects on the kidney and posterior lobe of the hypophysis. It is possible that glucocorticoid therapy needs to be supported by other immunomodulatory therapies to have an effect on all affected organs.

Renal infarct volume and renal function decline in acute and chronic phases.

BACKGROUND: Acute renal infarction (ARI) is a rare disease. ARI causes decline in renal function in both the acute and chronic phases. However, the correlation between the volume of the infarction and degree of renal function decline has not been fully investigated. Therefore, we aimed to examine the relationship between the volume of the infarction and degree of renal function decline. METHODS: We performed a single-center, retrospective, observational study investigating clinical parameters and the volume of the infarction. The volume of the infarction was measured using reconstructed computed tomography data. RESULTS: A total of 39 patients (mean age, 72.6 ± 13.2 years; men, 59%) were enrolled. The median infarction volume was 45 mL (interquartile range, 14-91 mL). The volume of the infarction was significantly associated with the peak lactate dehydrogenase (LDH) level (median, 728 IU/L; interquartile range, 491-1227 U/L) (r = 0.58, p < 0.01) and the degree of renal function decline in both acute and chronic phases (r = -0.44, -0.38, respectively, p < 0.05). The peak LDH level was significantly correlated with the degree of renal function decline in the acute phase but not in the chronic phase (r = -0.35, -0.21; p < 0.05, N.S., respectively). CONCLUSIONS: The volume of the infarction may be a factor in the degree of renal function decline in ARI. Therefore, assessment of infarct volume in ARI is important.

Mitochonic Acid 5 (MA-5), a Derivative of the Plant Hormone Indole-3-Acetic Acid, Improves Survival of Fibroblasts from Patients with Mitochondrial Diseases.

Mitochondria are key organelles implicated in a variety of processes related to energy and free radical generation, the regulation of apoptosis, and various signaling pathways. Mitochondrial dysfunction increases cellular oxidative stress and depletes ATP in a variety of inherited mitochondrial diseases and also in many other metabolic and neurodegenerative diseases. Mitochondrial diseases are characterized by the dysfunction of the mitochondrial respiratory chain, caused by mutations in the genes encoded by either nuclear DNA or mitochondrial DNA. We have hypothesized that chemicals that increase the cellular ATP levels may ameliorate the mitochondrial dysfunction seen in mitochondrial diseases. To search for the potential drugs for mitochondrial diseases, we screened an in-house chemical library of indole-3-acetic-acid analogs by measuring the cellular ATP levels in Hep3B human hepatocellular carcinoma cells. We have thus identified mitochonic acid 5 (MA-5), 4-(2,4-difluorophenyl)-2-(1H-indol-3-yl)-4-oxobutanoic acid, as a potential drug for enhancing ATP production. MA-5 is a newly synthesized derivative of the plant hormone, indole-3-acetic acid. Importantly, MA-5 improved the survival of fibroblasts established from patients with mitochondrial diseases under the stress-induced condition, including Leigh syndrome, MELAS (myopathy encephalopathy lactic acidosis and stroke-like episodes), Leber's hereditary optic neuropathy, and Kearns-Sayre syndrome. The improved survival was associated with the increased cellular ATP levels. Moreover, MA-5 increased the survival of mitochondrial disease fibroblasts even under the inhibition of the oxidative phosphorylation or the electron transport chain. These data suggest that MA-5 could be a therapeutic drug for mitochondrial diseases that exerts its effect in a manner different from anti-oxidant therapy.

Conformational change in transfer RNA is an early indicator of acute cellular damage.

Tissue damage by oxidative stress is a key pathogenic mechanism in various diseases, including AKI and CKD. Thus, early detection of oxidative tissue damage is important. Using a tRNA-specific modified nucleoside 1-methyladenosine (m1A) antibody, we show that oxidative stress induces a direct conformational change in tRNA structure that promotes subsequent tRNA fragmentation and occurs much earlier than DNA damage. In various models of tissue damage (ischemic reperfusion, toxic injury, and irradiation), the levels of circulating tRNA derivatives increased rapidly. In humans, the levels of circulating tRNA derivatives also increased under conditions of acute renal ischemia, even before levels of other known tissue damage markers increased. Notably, the level of circulating free m1A correlated with mortality in the general population (n=1033) over a mean follow-up of 6.7 years. Compared with healthy controls, patients with CKD had higher levels of circulating free m1A, which were reduced by treatment with pitavastatin (2 mg/d; n=29). Therefore, tRNA damage reflects early oxidative stress damage, and detection of tRNA damage may be a useful tool for identifying organ damage and forming a clinical prognosis.

Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3.

The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1, following the reduction of plasma level of guanidinosuccinate. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD.

Transcriptional regulation of organic anion transporting polypeptide SLCO4C1 as a new therapeutic modality to prevent chronic kidney disease.

Uremic toxins accumulate in patients with chronic kidney diseases (CKDs) and cause further progression of renal damage and cardiovascular diseases. Recently, it was reported that some of the organic anion transporting polypeptides (OATPs) and the organic anion transporters (OATs) are involved in the renal elimination of uremic toxins. SLCO4C1 is the only OATP expressed at the basolateral side of proximal tubular cells in human kidney, and it mediates the excretion of uremic toxins. The overexpression of human SLCO4C1 in rat kidney promotes the renal excretion of uremic toxins and reduces hypertension, cardiomegaly, and renal inflammation in renal failure. Statins induce SLCO4C1 expression thorough transcriptional factor Aryl hydrocarbon receptor through binding of the xenobiotic responsive element at its promoter region. The administration of statin in a rat renal failure model facilitated the elimination of uremic toxins and mitigated organ damage. In addition, metabolomic analysis of rat renal failure models and patients with CKD by capillary electrophoresis-mass spectrometry is a useful method for identifying new uremic solutes and explores surrogate biomarkers for detecting the progression of early stage CKD.

Metabolomic profiling of the autosomal dominant polycystic kidney disease rat model.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is an inherited systemic disease characterized by renal cyst expansion, resulting in renal failure. With the progression of renal damage, the accumulation of uremic compounds is recently reported to subsequently cause further renal damage and hypertension. Finding uremic toxins and sensitive markers for detecting the early stage of ADPKD is necessary to clarify its pathophysiological process and to prevent its progression. The aim of this study was to analyze the profile of uremic retention solutes of ADPKD by capillary electrophoresis-mass spectrometry (CE-MS) using the Han:SPRD rat model. METHODS: Two hundred and ninety-seven cations and 190 anions were comprehensively analyzed by CE-MS in Han:SPRD rats and control rats. RESULTS: We found 21 cations and 19 anions that accumulated significantly in the heterozygous (Cy/+) ADPKD rat model compared with control rats. Among the compounds, increases in 5-methyl-2'-deoxycytidine, glucosamine, ectoine, allantoate, α-hydroxybenzoate, phenaceturate and 3-phenylpropionate and decreases in 2-deoxycytidine, decanoate and 10-hydroxydecanoate were newly identified in the ADPKD Cy/+ rats. CONCLUSION: We identified uremic retention solutes in ADPKD Cy/+ rats. Compounds related to ADPKD could be useful markers for detecting the early stage of ADPKD.

The HMG-CoA reductase inhibitor pravastatin stimulates insulin secretion through organic anion transporter polypeptides.

The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin has been reported to have a beneficial effect on reducing the new onset of diabetes as well as lowering plasma lipids. Because pravastatin is a water-soluble organic anion, it cannot easily penetrate the lipid bilayer of the cell membrane. As the precise mechanisms of the effect of pravastatin on glucose metabolism and diabetes have not been clarified, we examined the roles of the organic anion transporter family on pravastatin-treated islet and adipocyte functions. Rat oatp1/slco1a1, oatp2/slco1a4 and oatp3/slco1a5 were expressed in the pancreas, and rat oatp3/slco1a5 was also detected in rat insulinoma cell line INS-1e. Pravastatin was transported not only by oatp1/slco1a1 and oatp2/slco1a4, but also by rat oatp3/slco1a5. Pravastatin uptake into INS-1e cells was detected and this transport was inhibited by sulfobromophthalein and rifampicin, both of which are known to inhibit oatp family-mediated uptake. In addition, pravastatin enhanced the glucose-stimulated insulin secretion from INS-1e cells. When fat-loaded db/db mice were treated with pravastatin, glucose intolerance and insulin resistance were prevented. In addition, insulin secretion from isolated islets was enhanced by pravastatin. These data suggest that pravastatin has pleiotropic effects on islets through membrane transport under high fat/glucose conditions.