Inhibition of CEACAM1 expression in cytokine-activated neutrophils using JAK inhibitors.

OBJECTIVES: Carcinoembryonic-antigen-related cell-adhesion molecule 1 (CEACAM1) is an adhesion molecule that acts as a coinhibitory receptor in the immune system. We previously demonstrated that CEACAM1 is predominantly expressed on peripheral blood neutrophils in patients with RA. The aim of the present study was to investigate the effects of Janus kinase inhibitors (JAKi) on cytokine-activated human neutrophils and CEACAM1 expression. METHODS: Peripheral blood neutrophils were obtained from healthy subjects. Isolated neutrophils were stimulated with tumor necrosis factor-alpha (TNF-α) or granulocyte-macrophage colony-stimulating factor (GM-CSF) in the presence or absence of JAKi. The expression of CEACAM1 in peripheral blood neutrophils was analyzed by flow cytometry. Protein phosphorylation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 was assessed by western blot using phospho-specific antibodies. RESULTS: We found that TNF-α-induced CEACAM1 expression was marginally suppressed after pretreatment with pan-JAK inhibitor, tofacitinib. Moreover, TNF-α induced STAT1 and STAT3 phosphorylation at the late stimulation phase (4 to 16 h). The expressions of CEACAM1 on neutrophils were markedly up-regulated by GM-CSF not by interleukin (IL)-6 stimulation. All JAKi inhibited GM-CSF-induced CEACAM1 expressions on neutrophils, however, the inhibitory effects of baricitinib were larger compared to those of tofacitinib or filgotinib. Moreover, CEACAM1 was marginally upregulated in interferon (IFN)-γ stimulated neutrophils. Similarly, JAKi inhibited IFN-γ-induced CEACAM1 expressions on neutrophils. CONCLUSIONS: We demonstrated that JAKi prevent GM-CSF-induced CEACAM1 expression in neutrophils, and JAKi-induced inhibition depends on their selectivity against JAK isoforms. These findings suggest that JAKi can modulate the expression of CEACAM1 in cytokine-activated neutrophils, thereby limiting their activation.

Picosecond Trajectory of Two-Dimensional Vortex Motion in FeSe_{0.5}Te_{0.5} Visualized by Terahertz Second Harmonic Generation.

We have investigated the vortex dynamics in a thin film of an iron-based superconductor FeSe_{0.5}Te_{0.5} by observing second-harmonic generation (SHG) in the terahertz frequency range. We visualized the picosecond trajectory of two-dimensional vortex motion in a pinning potential tilted by Meissner shielding current. The SHG perpendicular to the driving field is observed, corresponding to the nonreciprocal nonlinear Hall effect under the current-induced inversion symmetry breaking, whereas the linear Hall effect is negligible. The estimated vortex mass, as light as a bare electron, suggests that the vortex core moves independently from quasiparticles at such a high frequency and large velocity ≈300 km/s.

Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

Atypical Familial Mediterranean Fever Presenting with Recurrent Upper Back Pain: A Case Report.

Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease that is characterized by recurrent episodes of fever, serositis, and synovitis. FMF synovitis attacks resemble the clinical presentation of acute monoarthritis with pain and hydrarthrosis, which always resolve spontaneously. In most cases, colchicine will prevent these painful arthritis attacks in FMF. However, distinguishing these arthritis episodes from other febrile attacks with various clinical manifestations, including serositis, is important. We describe a Japanese patient with FMF who presented a febrile attack with severe abdominal and upper back pain (peri-scapula lesion), without any other joint involvement. A 44-year-old female patient presented with recurrent episodes of fever with abdominal and back pain. She carried heterozygous variants in exon 3 of the MEFV gene (P369S/R408Q). She was diagnosed with FMF according to Tel-Hashomer's diagnostic criteria for FMF. Colchicine treatment improved her febrile attcks with peritonitis, however, severe back pain was sustained. This unique aspect of severe pain attack was successfully resolved by canakinumab treatment, which is a specific interleukin-1ß monoclonal antibody, and was finally diagnosed as FMF-related shoulder joint synovitis. Further investigations were needed to evaluate the effectiveness of interleukin-1 antagonists against colchicine-resistant arthritis in FMF patients.

Rapid Clinical Improvement of Multicentric Castleman Disease (MCD) with Renal Involvement Following Treatment with Tocilizumab: AA Amyloidosis as a Possible Renal Involvement of MCD.

Castleman disease (CD) is a lymphoproliferative disorder that manifests as hypergammaglobulinemia and severe inflammation with multiorgan involvement. However, renal involvement has been infrequently described in CD. We present a case of a 63-year-old Japanese male patient with multicentric CD (MCD) in whom kidney involvement, including impaired renal function and massive proteinuria, is present. He had a 2-year history of inflammatory arthritis and was referred to our clinic with newly developed proteinuria, renal dysfunction, and elevated levels of acute-phase proteins. Abdominal computed tomography scan revealed hepatosplenomegaly, including mesenteric and inguinal lymph node enlargements. The patient underwent inguinal lymph node resection. Excisional biopsy of the inguinal lymph node showed multiple lymphoid follicles and expansion of interfollicular areas by marked plasmacytosis consistent with mixed type CD. The patient was diagnosed with human herpes virus 8-negative MCD according to the international diagnostic criteria for CD. Diagnostic renal biopsy was not performed following the medical viewpoint. Tocilizumab (TCZ) treatment was highly effective in reducing proteinuria and stabilizing renal function, as well as improving other clinical symptoms. The patient responded to TCZ treatment, and the renal involvement was rapidly improved. Our preliminary immunohistochemical analysis indicated AA amyloid deposits in urinary epithelial cells suggesting a possible renal involvement of AA amyloidosis. TCZ could potentially be one of the therapeutic options in patients with MCD with renal involvement.

Development of Acute Promyelocytic Leukemia in a Patient with Granulomatosis with Polyangiitis: A Case Report.

Granulomatosis with polyangiitis (GPA) is a rare disorder of unknown etiology, which is characterized by necrotizing granulomatous inflammation of the upper respiratory system and kidneys. Immunosuppressive treatment (cyclophosphamide or azathioprine with glucocorticoids) improved the outcome of GPA, however, latent comorbidity (cancers and hematologic malignancies) has become more prevalent in recent years. Here, we present a first case of the patient with GPA complicated by acute promyelocytic leukemia (APL) successfully treated with molecular-targeted therapy. A 77-year-old female was referred to our hospital for nasal obstruction, hearing loss, and fever. Otorhinolaryngological investigation revealed otitis media, and head computed tomography (CT) showed paranasal mucosal thickening with septal perforation. Chest CT showed cavitary granulomatous lesions in both lungs. Biopsy of the nasal mucosa revealed granulomatous lesions, and the patient was finally diagnosed with GPA. Oral administration of prednisolone 50 mg/day was initiated, and oral azathioprine (50 mg/day) was added. After 26 months of azathioprine initiation, pancytopenia developed and azathioprine was stopped. Then sudden elevated levels of blasts appeared in the hemogram (blasts 11%). She was diagnosed with APL via bone marrow examination which revealed plenty of faggot cells with Auer rods and chromosomal mutation. The patient was started on all-trans retinoic acid 60 mg/day following arsenic trioxide 7 mg/day in consideration of elderly onset. Complete remission was achieved and oral prednisolone was successfully reduced to 15 mg/day without a major relapse of GPA. Because GPA can be complicated by APL even during maintenance treatment using azathioprine, careful monitoring should be performed in such patients.

Outcome of rituximab treatment in Japanese patients with ANCA-associated vasculitis in daily clinical practice: A two-centre study in Fukushima, Japan.

OBJECTIVES: Rituximab (RTX) efficacy for anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has been reported in large randomized studies; however, the efficacy of RTX in Japanese AAV patients, especially the elderly, is not well known. We aimed to determine the clinical efficacy of RTX in Japanese AAV patients including elderly patients. METHODS: This study included 78 AAV patients newly diagnosed with AAV and treated in Fukushima Medical University Hospital or Ohta-Nishinouchi Hospital from April 2004 to September 2019. Clinical records were retrospectively reviewed, and clinical efficacy and outcome (1-year survival) between the RTX treatment group (23 cases) and the conventional therapy group (immunosuppressive therapy other than RTX, 55 cases) were compared. We also analysed the clinical efficacy and outcome in elderly-onset (>75 years) AAV patients. RESULTS: The RTX group showed similar efficacy and 1-year survival compared to the conventional therapy group. Conversely, after 6 months of treatment, prednisolone doses significantly decreased in the RTX group compared to the conventional therapy group (p < 0.01). In the elderly-onset AAV patients, clinical efficacy and outcome were not significantly different. CONCLUSIONS: RTX was effective in Japanese AAV patients and may be useful for prompt tapering of prednisolone doses, even in elderly-onset AAV patients.

Effectiveness of combination tocilizumab and glucocorticoids as an induction therapy in patients with Takayasu arteritis: An observational study.

BACKGROUND: The efficacy of tocilizumab (TCZ) in the treatment of Takayasu arteritis (TA) was demonstrated in randomized controlled trials. The objective of this study was to analyse the effectiveness of combining TCZ with glucocorticoids (GC) as induction therapy in patients with TA. METHOD: This was a retrospective observational study including 32 patients with newly diagnosed TA. Clinical effectiveness of TCZ in maintaining relapse-free remission and GC-tapering were compared between patients who were treated with TCZ plus GC and those who were treated with GC with or without immunosuppressants. RESULTS: The study comprised 32 patients (27 women/5 men) with a median age of 25.5 years (range, 13-72). In the TCZ group (n = 14), patients received TCZ in combination with GC as an induction therapy. In the non-TCZ group (n = 18), patients were treated with single-agent GC or GC plus immunosuppressant. In the matched analysis, relapse-free survival rate was significantly higher in the TCZ group as compared to the non-TCZ group during GC taper. CONCLUSION: TCZ, in combination with GC, would be an effective alternative induction regimen for patients with TA.

Anti-Mi-2 and Anti-TIF1-γ Double-Positive Juvenile Dermatomyositis Treated under Diagnosis of Chronic Eczema: A Case Report.

Myositis-specific autoantibodies are relevant factors that define the disease phenotype of dermatomyositis (DM). Anti-Mi-2 antibody-positive DM patients may present with the typical skin lesions and prominent myositis. On the other hand, adult DM patients with anti-TIF-γ antibody seem to be associated with internal malignancy. Here, we report a rare case of juvenile dermatomyositis (JDM) exhibiting anti-Mi-2 and anti-transcriptional intermediary factor-1 gamma (TIF1-γ) antibodies, with no internal malignancy. A 16-year-old female Japanese patient under treatment with a 2-year history of chronic eczematous lesions was admitted to our department with elevated levels of muscle enzymes. Characteristic skin changes, such as Gottron's papules of the hand, heliotrope rash of the eyelids, and poikiloderma-like legions and diffuse pigmentation on the back, were observed. Histologically, the patient's skin was characterized by the presence of lymphocytic vascular inflammation and endothelial swelling, which are consistent with DM. Severe symmetric proximal muscle weakness, elevated serum muscle enzymes and the presence of anti-TIF1-γ and Mi-2 antibodies were noted. The diagnosis of JDM was made according to the European League Against Rheumatism (EULAR) diagnostic criteria. A high dose of corticosteroids and following intravenous cyclophosphamide treatment (750 mg three times) resulted in an improvement in clinical manifestations and functional outcomes, and recurrence did not occur. Estimation of autoantibodies may serve as an ancillary tool in delineating and defining distinct clinical phenotypes in JDM.

Total Hip Joint Replacement in a Patient with Colchicine-Resistant Familial Mediterranean Fever under Canakinumab Treatment.

Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disease characterized by recurrent episodes of fever and serositis. Periodic febrile attack can be managed with biologic medication in colchicine-resistant FMF patients, however, no reports or guidelines exist regarding the postoperative management of elective joint surgery in these patients. Although it is not clear how FMF attacks are triggered, they may be precipitated by stress including anesthesia or surgery. This study reports the case of a 51-year-old FMF patient who received total hip replacement under canakinumab (a specific interleukin-1ß monoclonal antibody) treatment. He had highly active FMF, which was resistant to colchicine; however, his recurrent febrile attack with serositis was successfully controlled with canakinumab. Four months later from the start of canakinumab treatment, his hip osteoarthritis was required for total hip replacement (THR) because of the traumatic fracture. THR was successfully done and FMF attack was not occurred after this elective surgery. Discontinuation of canakinumab 3 weeks before surgery and resumption 6 weeks after led to favorable outcome without complications. This case addresses the differential management concerning stopping and restating of canakinumab in the perioperative setting in contrast to the other biologics such as tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) blocking agents. This case report suggests that canakinumab may represent a safe and effective therapy for the colchicine-resistant FMF, even in the patients requiring THR therapy.

A case of Schnitzler's syndrome without monoclonal gammopathy successfully treated with canakinumab.

BACKGROUND: Schnitzler's syndrome (SchS) is a rare autoinflammatory syndrome with diagnostic challenge and be characterized by chronic urticaria, a monoclonal gammopath, periodic fever and bone pain. In addition to the monoclonal gammopathy, bone abnormalities are often found at the site of bone pain in patients with SchS. The remarkable efficacy of interleukin-1 (IL-1) inhibition was also demonstrated in this syndrome. CASE PRESENTATION: We describe a case of refractory chronic urticaria presenting with clinical manifestations consistent with SchS without monoclonal gammopathy. A 43-year-old female patient suffering from recurring of urticaria with periodic fever as well as bone pain for the past 4 years. The patient had leukocytosis and elevated levels of C-reactive protein (CRP) and serum amyloid A (SAA). PET/CT (positron emission tomography/computed tomography) and MRI (magnetic resonance imaging) examination revealed hyper-metabolism areas in both femoral bone marrow. Although bone marrow histology revealed no abnormality, urticarial skin lesions shows neutrophilic infiltrations without evidence of vasculitis. We could not exclude the possibility of SchS. The patient had been treated with antihistamines, steroids, omarizumab, colchicine and cyclosporine A, no therapeutic effect was observed. She was started on canakinumab 150 mg subcutaneous injection with 4 weeks interval. Within 48 h after the first injection, the urticarial rash disappeared, and febrile attack and bone pain had not recurred. Elevated levels of serum CRP and SAA were normalized within a week after the first injection of canakinumab. CONCLUSIONS: The current case suggests an important role for IL-1 as a mediator in the pathophysiology of SchS-like refractory urticaria with bine pain. It had been presumed that monoclonal gammopathy may not always present in SchS. It is important to avoid delay in diagnosis and initiation of proper treatment in SchS or autoinflammatory conditions resembling SchS.

Hemophagocytic Lymphohistiocytosis Associated with Disseminated Nontuberculous Mycobacterial Infection in a Patient with Mesenteric Panniculitis.

Mesenteric panniculitis is a chronic inflammatory disease characterized by non-specific inflammation of the adipose tissue in the mesentery. Hemophagocytic lymphohistiocytosis is a life-threating disease associated with aberrant macrophage overactivation, in which infections can be a leading cause in immunocompromised hosts. Here, we report a rare case of mesenteric panniculitis and hemophagocytic lymphohistiocytosis complicated by disseminated Mycobacterium intracellulare. A 71-year-old male with mesenteric panniculitis was admitted to our hospital for fever and pancytopenia. He was treated with oral prednisolone (15 mg/day) and cyclosporin A (150 mg/day) at presentation. Physical and laboratory examinations revealed disseminated infection with nontuberculous mycobacteria; Mycobacterium intracellulare was detected in cultures of cerebrospinal fluid, blood, sputum, and gastric fluid. Patient signs and symptoms fulfilled the five criteria for a diagnosis of hemophagocytic lymphohistiocytosis, including fever, cytopenia, hemophagocytosis, hyperferritinemia, and high soluble interleukin-2 receptor levels. Therefore, the diagnosis of nontuberculous mycobacteria-associated hemophagocytic lymphohistiocytosis was established. An anti-mycobacterial chemotherapy including chloramphenicol (800 mg/day), rifampin (450 mg/day) and ethambutol (750 mg/day) together with streptomycin (750 mg twice per week) was initiated at 30 days after admission; maintenance doses of prednisolone were increased to 60 mg/day. Fever and pancytopenia improved in response to anti-mycobacterial chemotherapy. The present case suggests that mesenteric panniculitis could be complicated with hemophagocytic lymphohistiocytosis caused by immunosuppressive therapy-associated infections as well as underlying disease activity. In conclusion, the possibility of disseminated nontuberculous mycobacteria infection with hemophagocytic lymphohistiocytosis should be considered if unexplained fever or hematological dyscrasia were presented in patients of mesenteric panniculitis.

Adult-Onset Still's Disease Complicated by Immunoglobulin A Vasculitis and anti-CCP Antibody-Positive Arthritis.

A 38-year-old male was admitted to our hospital for arthralgia, fever, skin rash, and purpura. He was diagnosed as having adult-onset Still's disease (AOSD) based on Yamaguchi's criteria. Skin biopsy revealed immunoglobulin A (IgA) vasculitis. He was also found to have anti-cyclic citrullinated peptide (CCP) antibody-positive inflammatory arthritis on a shoulder joint, however he did not fulfill classification criteria for rheumatoid arthritis. Elevated serum cytokine such as serum IL-18 supported the diagnosis of AOSD. His symptoms improved with 40 mg of prednisolone plus cyclosporin A (200 mg/day). Two years after hospitalization, AOSD was relapsed with pleurisy and hyperferritinemia. Finally, he was diagnosed with multicyclic systemic type of AOSD complicated by IgA vasculitis and seropositivity of anti-CCP antibody. Clinicians need to consider the complication of multiple rheumatic diseases, even if the disease-specific autoantibody is positive.

Vascular Behcet's Disease Preceded by Fever of Unknown Origin: Usefulness of Ultrasonography for the Detection of Large-Vessel Vasculitis.

Behcet's disease is a systemic vasculitis characterized by oral and genital ulcers, erythema nodosum, and ocular involvement. Fever of unknown origin is a relatively rare event in Behcet's disease. We present the case of a 17-year-old male patient who suffered from prolonged fever for two months. The patient tested positive for HLA-B52 and levels of acute phase reactants were elevated. He complained of sore throat and neck pain that were evaluated by cervical ultrasonography, which revealed thickening of the carotid arterial wall and narrowing of the vessel lumen. The patient was diagnosed with vascular Behcet's disease and treated with glucocorticoid, which improved the clinical symptoms and thickening of the carotid arterial wall as detected by color duplex ultrasonography. Since vascular Behcet's disease may lead to morbidity and mortality, we suggest the early use of ultrasonography to help detect medium/large-vessel vasculitis. Prolonged fever in patients with Behcet's disease should be promptly evaluated for vascular involvement.

Immunoglobulin A Vasculitis in a Japanese Patient with Complete Familial Mediterranean Fever Carrying MEFV Exon 10 Mutation.

Immunoglobulin A (IgA) vasculitis is a systemic small-vessel vasculitis involving the skin, kidney, joints, and gastrointestinal tract. Familial Mediterranean fever (FMF) is the most common autoinflammatory disease characterized by periodic fever, peritonitis, pleuritis, or arthritis. It is well known that FMF may coexist with vasculitis, especially small and medium vessel vasculitis. Here we present a Japanese male patient with FMF who later developed IgA vasculitis and a relapsing disease course. A 51-year-old Japanese male was referred because of upper abdominal pain, arthralgia, and bilateral purpura of the lower limbs. He fulfilled the criteria for IgA vasculitis, which was successfully treated by corticosteroid and immunosuppressive therapy. He had a medical history of periodic fever since the age of 10 years old. The Mediterranean fever (MEFV) gene analysis revealed that he was heterozygous for M694I and E148Q mutations. Colchicine therapy resolved his periodic febrile attacks. To our knowledge, coexistence of FMF with IgA vasculitis has not been reported in East Asia, including Japan. Our case suggests that MEFV gene exon 10 mutations could be related to the development of IgA vasculitis and affects its clinical course.

Uric acid-mediated inflammasome activation in IL-6 primed innate immune cells is regulated by baricitinib.

OBJECTIVES: Gout is an inflammatory arthropathy caused by the deposition of monosodium urate (MSU). The synthesis and release of IL-1ß is crucial for MSU-induced synovial inflammation. The aim of the present study was to investigate the mechanism of MSU crystal-induced autoinflammatory processes. METHODS: In vitro studies were used to evaluate the role of IL-6 in inflammasome activation in human neutrophils cultured with MSU crystals. Human neutrophils were stimulated with MSU in the presence or absence of IL-6 priming to determine NLRP3 inflammasome activation and subsequent cleaved caspase-1 induction or IL-1ß production. RESULTS: IL-6 or MSU stimulation alone did not result in the efficient IL-1ß production from human neutrophils. However, MSU stimulation induced marked IL-1ß production from IL-6-primed neutrophils. Pretreatment with baricitinib, which blocks IL-6 receptor signaling, prevented MSU-induced cleaved caspase-1 or IL-1ß induction in IL-6-primed neutrophils. Tocilizumab pretreatment also inhibited MSU-mediated IL-1ß production from IL-6-primed neutrophils. CONCLUSION: Priming of human neutrophils with IL-6 promotes uric acid-mediated IL-1ß secretion in the absence of microbial stimulation. These results suggest that an endogenous cytokine, IL-6, is involved in MSU-mediated NLRP3 inflammasome activation and subsequent IL-1ß production from innate immune cells and has a crucial role in MSU crystal-induced synovial inflammation. These findings provide insights into uric acid-mediated autoinflammation in the innate immune system.

Sustained Long-Term Retention Rates of Abatacept in Combination with Conventional Synthetic Disease-Modifying Antirheumatic Drugs in Elderly Patients with Rheumatoid Arthritis.

Background and Objectives: Treatment for elderly (aged ≥75 years) patients with rheumatoid arthritis (RA) is important because they usually have several complications and organ dysfunction and are more susceptible to drug-related adverse events. Abatacept (ABT) treatment is relatively safe in elderly RA patients; however, the real-world data of efficacy and long-term retention of ABT is sparse in such patients. This study aimed to investigate the clinical efficacy and long-term retention rates of ABT in elderly Japanese RA patients. Materials and Methods: This 10-year retrospective observational cohort study was performed in two centers in Fukushima, Japan. We reviewed the clinical features of elderly RA patients who received ABT and investigated the differences in retention rates with concomitant administration of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Results: The clinical characteristics of younger (<75 years old, 39 cases) and elderly (≥75 years old, 20 cases) RA patients were generally similar. Although the efficacy was also similar, the concomitant administration of csDMARDs with ABT differed between the two groups. Younger patients significantly decreased methotrexate (MTX) administration than elderly patients (p < 0.01), and elderly patients significantly received tacrolimus (TAC) (p < 0.01) or salazosulfapyridine (SASP; p = 0.01) than younger patients. The overall retention and infection-free survival rates were similar between the two groups. Conclusion: Elderly RA patients showed sustained retention rates compared to younger RA patients. TAC and SASP can help to maintain sustained retention rates in elderly RA patients.

JAK inhibitors impair GM-CSF-mediated signaling in innate immune cells.

BACKGROUND: Innate immune cells play a crucial role in the pathophysiology of rheumatoid arthritis (RA) via release of cytokines. Small-molecule inhibitors of Janus kinases (JAKi) are clinically efficacious in patients with RA. However, the isoform-specific action of each JAKi is difficult to assess, since JAKs form heterodimeric complexes with cytokine receptors. We assessed the effects of several JAKi on GM-CSF-primed human innate immune cells. RESULTS: Treatment with JAKi (tofacitinib, baricitinib, upadacitinib) prevented GM-CSF-induced JAK2/STAT5 phosphorylation at higher concentrations (400 nM) in THP-1 cells. Whereas compared with baricitinib or upadacitinib, the inhibitory effects of tofacitinib on the GM-CSF-induced JAK2/STAT5 phosphorylation were weak at lower concentrations (≤ 100 nM). All JAKi inhibited GM-CSF-induced IL-1ß production by human neutrophils. However, the inhibitory effects of baricitinib on IL-1ß production were larger compared to those of tofacitinib or upadacitinib at lower concentrations (≤ 100 nM). Similarly, all JAKi inhibited GM-CSF-induced caspase-1(p20) production by human neutrophils. CONCLUSION: We conclude that incubation with JAKi prevents GM-CSF-mediated JAK2/STAT5 activation in human innate immune cells. Although baricitinib and upadacitinib almost completely blocked GM-CSF-mediated JAK2/STAT5 signaling, the inhibitory effects of tofacitinib were weaker at lower concentrations suggesting that variation exists among these JAKi in the inhibition of JAK2 signaling pathways.

Association between variations in the number of hospital beds and inpatient chemo/radiotherapy for breast cancer: a study using a large claim database.

OBJECTIVE: Chemo/radiotherapy for breast cancer patients does not require hospitalisation in most cases. We investigated the relationship between the proportion of hospitalisation for chemo/radiotherapy over total hospitalisation and the number of hospital beds per capita among breast cancer cases. DESIGN: A retrospective observational study. SETTING: Hospitals in Japan. PARTICIPANTS: In total, 561,165 records of hospitalisation of breast cancer cases were extracted from the Japanese Diagnosis Procedure Combination database from April 2012 to March 2016.Intervention(s) and main outcome measure(s): A multivariable beta regression model accounting for the clustering effect within each prefecture was used to examine the relationship between the number of hospital beds per capita in each prefecture and the proportion of hospitalisation for inpatient chemo/radiotherapy treatment or the number of surgical operations for breast cancer patients in each prefecture. RESULTS: The proportion of hospitalisation for inpatient chemo/radiotherapy treatment varied from 2.6% to 61.8% in 2016. The logit proportion of hospitalisation for inpatient chemo/radiotherapy treatment was significantly higher for every additional hospital bed per capita (0.0027, 95% confidence interval (95% CI) 0.0014-0.0040). In contrast, no significant relationship was observed between the number of surgical operations for breast cancer per capita and the number of hospital beds per capita. CONCLUSIONS: We found that a higher number of regional hospital beds were associated with a higher proportion of hospitalisation for chemo/radiotherapy treatment, suggesting that inpatient chemo/radiotherapy may be a provider-induced practice.

IgG4-Related Disease Complicated by Brain Parenchymal Lesions Successfully Treated with Corticosteroid Therapy: A Case Report.

Immunoglobulin G4 (IgG4)-related disease (IgG4-RD) is distinguished by the infiltration of IgG4-positive plasma cells in a variety of tissues and organs including the pancreas, salivary glands, retroperitoneal lesions, kidney, and lymph nodes with elevated serum IgG4 levels. Even so, central nervous system (CNS) lesions such as brain parenchymal lesions associated with IgG4-RD are scarce. So far, only six cases of IgG4-RD in relation with brain parenchymal lesions have been described, with its characteristics still being not clear. Here we have detailed a case of IgG4-RD with brain parenchymal lesions and reviewed previously-reported cases of IgG4-RD with brain parenchymal lesions. A 62-year-old Japanese male suffering from lung silicosis was admitted to our hospital for abdominal discomfort and altered consciousness. He has shown no major neurologic abnormalities except for drowsiness, urinary retention, and fecal incontinence. Brain magnetic resonance imaging has shown scattered hyperintense signals in the brain parenchyma. The serum IgG4 levels were elevated and systemic lymph nodes were enlarged. Biopsy from inguinal lymph nodes has shown massive infiltration of IgG4-positive plasma cells: the ratio of IgG4-positive/IgG-positive plasma cells was nearly 100%. Based on clinical courses, images, laboratory data, and pathological findings, a diagnosis of IgG4-RD that was complicated by brain parenchymal lesions and sacral nerve disturbance was confirmed. The patient was then given methylprednisolone pulse therapy (1g for 3 days) succeeding oral prednisolone (1 mg per body weight). The clinical and radiological improvements together with steroid therapy proposed IgG4-RD to be the cause of the lesions.