Genetic and chemical inhibition of IRF5 suppresses pre-existing mouse lupus-like disease.

The transcription factor IRF5 has been implicated as a therapeutic target for the autoimmune disease systemic lupus erythematosus (SLE). However, IRF5 activation status during the disease course and the effects of IRF5 inhibition after disease onset are unclear. Here, we show that SLE patients in both the active and remission phase have aberrant activation of IRF5 and interferon-stimulated genes. Partial inhibition of IRF5 is superior to full inhibition of type I interferon signaling in suppressing disease in a mouse model of SLE, possibly due to the function of IRF5 in oxidative phosphorylation. We further demonstrate that inhibition of IRF5 via conditional Irf5 deletion and a newly developed small-molecule inhibitor of IRF5 after disease onset suppresses disease progression and is effective for maintenance of remission in mice. These results suggest that IRF5 inhibition might overcome the limitations of current SLE therapies, thus promoting drug discovery research on IRF5 inhibitors.

A bacterial endo-ß-1,4-glucuronan lyase, CUL-I from Brevundimonas sp. SH203, belonging to a novel polysaccharide lyase family.

Cellouronate is a (1,4)-ß-D-glucuronan prepared by TEMPO-mediated oxidation from regenerated cellulose. We have previously isolated a cellouronate-degrading bacterial strain, Brevundimonas sp. SH203, that produces a cellouronate lyase (ß-1,4-glucuronan lyase, CUL-I). In this study, the gene encoding CUL-I was cloned, and the recombinant enzyme was heterologously expressed in Escherichia coli. The predicted CUL-I protein is composed of 426 amino acid residues and includes a putative 21-amino acid signal peptide. The recombinant CUL-I specifically depolymerized ß-1,4-glycoside linkages of cellouronate, and its mode of action was endo-type, like the native CUL-I. Sequence analysis showed CUL-I has no similarity to previously known polysaccharide lyases (PLs), indicating that CUL-I should be classified into a novel PL family.

Emotional resemblance: Perception of facial emotion in written English.

Written language is comprised of simple line configurations (i.e., letters) that, in theory, elicit affect by virtue of the concepts they symbolize, rather than their physical features. However, we propose that the line configurations that comprise letters vary in their visual resemblance to canonical features of facial emotion and, through such emotional resemblance, influence affective responses to written language. We first describe our data-driven approach to indexing emotional resemblance in each letter according to its visual signature. This approach includes cross-cultural validation and neural-network modeling. Based on the resulting weights, we examine the extent to which emotional resemblance in Latin letters is incidentally processed in a flanker paradigm (Study 1), shapes unintentional affective responses to letters (Study 2), accounts for affective responses to orthographically controlled letter strings (Study 3), and shapes affective responses to real English words (Study 4). Results were supportive of hypotheses. We discuss mechanisms, limitations, and implications. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Clinical significance of subcutaneous fat and fascial involvement in juvenile dermatomyositis.

Objectives: Subcutaneous involvement, including calcinosis and panniculitis, is a more common complication in juvenile dermatomyositis (JDM) than in adult dermatomyositis. Magnetic resonance imaging (MRI) is useful for evaluating disease distribution. We investigated the clinical significance of subcutaneous involvement in JDM. Methods: Thighs and hips in 18 newly diagnosed JDM patients were evaluated with fat-suppression MRI. Bilateral muscle, fascial and subcutaneous fat involvement were scored from 0 to 8 points according to the severity of distribution on MRI. Associations between clinical manifestations, serum muscle enzymes, and MRI scores were also evaluated. Results: Abnormal MRI findings in muscle, fascia and subcutaneous fat were observed in 18, 18, and 10 patients, respectively. Subcutaneous fat scores were significantly higher in early-diagnosed JDM patients (diagnosed less than 2 months from onset) than in late-diagnosed JDM patients (diagnosed later) (p = .025). Serum aldolase was elevated in all patients, although only eight demonstrated elevated serum creatine phosphokinase. Serum aldolase was significantly correlated with MRI scores for subcutaneous fat (p < .0001, ρ = .787) and fascia (p = .013 ρ = 0.574), but not muscle. Additionally, serum aldolase was significantly correlated with serum triglycerides (p = .009, ρ = 0.629). Conclusion: Subcutaneous fat involvement is a characteristic finding in early-diagnosed JDM and correlates with elevated serum aldolase.

Infliximab versus intravenous immunoglobulin for refractory Kawasaki disease: a phase 3, randomized, open-label, active-controlled, parallel-group, multicenter trial.

We compared the efficacy and safety of infliximab with intravenous immunoglobulin (IVIG), a standard therapy, in a phase 3 trial (NCT01596335) for Japanese patients with Kawasaki disease (KD) showing persistent fever after initial IVIG. Patients with initial IVIG-refractory KD, aged 1-10 years, received a single dose of IV infliximab 5 mg/kg or IV polyethylene glycol-treated human immunoglobulin (VGIH) 2 g/kg on day 0. Primary outcome was defervescence rate within 48 h after the start of treatment. Safety was evaluated through day 56. Overall, 31 patients were randomized (infliximab, n = 16; VGIH, n = 15); 31.3% and 60.0% patients discontinued due to worsening KD. Defervescence rate within 48 h was greater with infliximab (76.7%) than VGIH (37.0%) (p = 0.023), and defervescence was achieved earlier with infliximab (p = 0.0072). Coronary artery lesions occurred in 1 (6.3%) and 3 (20.0%) patients receiving infliximab and VGIH, respectively, up to day 21. Adverse events occurred in 15 (93.8%) and 15 (100.0%) patients in the infliximab and VGIH groups, respectively. No serious adverse events in the infliximab group and one in the VGIH group were observed. Infliximab improved the defervescence rate within 48 h and time to defervescence versus standard therapy, and was well tolerated in patients with IVIG-refractory KD.

Draft Genome Sequence of Brevundimonas sp. Strain SH203, Producing Cellouronate (ß-1,4-Linked Polyglucuronate) Lyase.

In this study, we report the draft genome sequence of Brevundimonas sp. strain SH203, which was previously isolated from natural soil and has the ability to degrade ß-1,4-polygluculonate (cellouronate). This genomic information may provide new insight into the mechanisms by which cellouronate is degraded.

PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis.

OBJECTIVE: Both genetic and environmental factors are associated with susceptibility to juvenile idiopathic arthritis (JIA). Many studies have reported that both a 'shared epitope' (SE) encoded by several HLA-DRB1 alleles and the peptidyl arginine deiminase type 4 (PADI4) gene polymorphisms are associated with susceptibility to rheumatoid arthritis (RA). However, it is uncertain whether JIA and RA share the latter genetic risk factor. Therefore, here we investigated relationships between HLA-SE and PADI4 polymorphisms with clinical subtypes of JIA. METHODS: JIA patients (39 oligoarthritis, 48 RF-positive polyarthritis, 19 RF-negative polyarthritis and 82 systemic) and 188 healthy controls were genotyped for HLA-DRB1 by PCR-sequence-specific oligonucleotide probe methodology. Three PADI4 gene single nucleotide polymorphisms (SNPs), rs2240340, rs2240337 and rs1748033, were genotyped using TaqMan SNP Genotyping Assays. RESULTS: Frequencies of the HLA-SE were higher in RF-positive polyarticular JIA than in healthy controls. RF-positive polyarticular JIA was associated with HLA-SE (OR = 5.3, 95% CI = 2.5-11.9, pc < 0.001). No associations were found between clinical subtypes of JIA and PADI4 allele frequency. Nonetheless, rs2240337 in the PADI4 gene was significantly associated with anti-cyclic citrullinated peptide antibody (ACPA)-positivity in JIA. The A allele at rs2240337 was a significant risk factor for ACPA positivity in JIA (OR = 5.6, 95% CI = 1.71-23.7 pc = 0.03). CONCLUSION: PADI4 gene polymorphism is associated with ACPA-positivity in JIA. The association of HLA-SE with RF-positive polyarticular JIA as well as RA is confirmed in Japanese. Thus, HLA-SE and PADI4 status both influence JIA clinical manifestations.

Characteristics of FDG-PET findings in the diagnosis of systemic juvenile idiopathic arthritis.

OBJECTIVE: To examine and delineate inflammatory focus in patients with juvenile idiopathic arthritis (JIA), (18)F-Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) ((18)F-FDG-PET) was applied to patients with JIA, and the images of these patients were compared. METHODS: Sixty-eight children (59 with systemic JIA (s-JIA) and 9 with polyarticular JIA) were included. The diagnosis of JIA was done to meet the International League of Associations for Rheumatology (ILAR) criteria. After 6-h fasting, whole-body positron emission tomography (PET) scans were acquired 60 min after intravenous injection of 3-5 MBq/kg (18)F-FDG. The interpretation of (18)F-FDG uptake was based on visual characteristics. RESULTS: Two types of PET images were outstanding in s-JIA; one was (18)F-FDG uptake in red bone marrow, such as the spine, pelvis, and long bones as well as spleen (12 cases), and other type was the uptake in the major joints, such as hips, elbows, wrists, knees, and ankles (8 cases). The former findings were correlated with elevated levels of inflammatory markers, while the latter were with significantly increased levels of MMP-3 (p < 0.05). CONCLUSION: There was a noticeable accumulation of (18)F-FDG uptake in bone marrow of s-JIA patients which may indicate the inflammatory focus of this disease and play an important role in the pathogenic basis of arthritis and systemic inflammation of s-JIA.

Usefulness of two interferon-γ release assays for rheumatic disease.

BACKGROUND: The aim of this study was to evaluate the performance of two interferon-γ release assays (IGRA), QuantiFERON-TB Gold In-Tube (QFT-GIT) and T-SPOT.TB, for pediatric patients with rheumatic disease in Japan and to analyze the frequencies of indeterminate test results with these kits. METHODS: An IGRA was performed in 108 patients <20 years old in order to exclude tuberculosis infection at the time of first application of or change of biological agents and immunosuppressants in Yokohama City University Hospital. RESULTS: None of the 108 patients tested had active tuberculosis during the 50 month observation period. Indeterminate results of QFT-GIT and T-SPOT.TB tests were obtained in 9.9% and in 0% of cases, respectively. Indeterminate results were obtained significantly more frequently in patients on prednisolone >0.5 mg/kg and in patients with active underlying disease. Use of biologicals and other immunosuppressants had no effect on these measurements. CONCLUSIONS: IGRA are very useful for excluding tuberculosis infection in patients with rheumatic disease before starting new immunosuppressant therapy. Furthermore, the T-SPOT.TB test was suitable for evaluating latent tuberculosis infection even under immunosuppression, when TB tests are generally hard to perform.

A national survey on current use of mycophenolate mofetil for childhood-onset systemic lupus erythematosus in Japan.

PURPOSE: To conduct a national survey of systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). Based on current information on the use of MMF, we aimed to evaluate its efficacy and safety for childhood-onset (c-) SLE. TARGET: We evaluated 115 patients by questionnaire on MMF use for c-SLE in medical facilities specializing in pediatric rheumatic and renal diseases. RESULTS: Average age at SLE onset was 10.6 (range, 2-15) years; average age at the time of starting MMF was 12.3 (range, 2-15) years. Average dose per body surface area was 1,059.3 mg/m(2)/day. Corticosteroid dosing was 20.9 mg/day before treatment but 7.7 mg/day after treatment. Laboratory values before and after MMF treatment were as follows: C3 increased from 67.0 to 84.9 mg/dl (p < 0.001), C4 increased from 10.2 to 15.1 mg/dl (p < 0.001), and anti-DNA antibody decreased from 154.2 to 18.4 IU/ml (p < 0.001). 24 adverse events in 21 cases were reported, but MMF was not discontinued in any. CONCLUSIONS: The amount of MMF for c-SLE in Japan is similar to the standard dose in other countries. Reduction of corticosteroid dose and improvement of laboratory values represent efficacy of MMF. The side effects recorded here indicated tolerability of the drug.

Somatic mosaicism for a NRAS mutation associates with disparate clinical features in RAS-associated leukoproliferative disease: a report of two cases.

RAS-associated leukoproliferative disease (RALD) is a newly classified disease; thus its clinical features and management are not fully understood. The cases of two patients with characteristic features of RALD are described herein. Patient 1 was a 5-month-old female with clinical features typical of autoimmune lymphoproliferative syndrome (ALPS) and markedly elevated TCRαß(+)CD4(-)CD8(-) T cell numbers. Genetic analyses failed to detect an ALPS-related gene mutation; however, whole exome sequencing and other genetic analyses revealed somatic mosaicism for the G13D NRAS mutation. These data were indivative of NRAS-associated RALD with highly elevated αß-double-negative T cells. Patient 2 was a 12-month-old girl with recurrent fever who clearly met the diagnostic criteria for juvenile myelomonocytic leukemia (JMML). Genetic analyses revealed somatic mosaicism, again for the G13D NRAS mutation, suggesting RALD associated with somatic NRAS mosaicism. Notably, unlike most JMML cases, Patient 2 did not require steroids or hematopoietic stem cell transplantation. Genetic analysis of RAS should be performed in patients fulfilling the diagnostic criteria for ALPS in the absence of ALPS-related gene mutations if the patients have elevated αß-double-negative-T cells and in JMML patients if autoimmunity is detected. These clinical and experimental data increase our understanding of RALD, ALPS, and JMML.

Pathogenesis of systemic inflammatory diseases in childhood: "Lessons from clinical trials of anti-cytokine monoclonal antibodies for Kawasaki disease, systemic onset juvenile idiopathic arthritis, and cryopyrin-associated periodic fever syndrome".

Inflammation has often been considered to be a nonspecific response and to play a bridging role in the activation of adaptive immunity. However, it is now accepted that inflammation is the product of an independent innate immune system closely linked to the adaptive immune system. The key mediators of inflammation are inflammatory cytokines, as determined by multiple lines of evidence both in vitro and in vivo. Due to the crucial role of inflammatory cytokines in the pathogenesis of autoimmune disorders, anti-cytokine treatment has been developed as a therapy for rheumatoid arthritis, juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases. We recently completed several clinical trials of anti-cytokine treatment for children with systemic inflammatory diseases: anti-IL-6 receptor monoclonal antibody (tocilizumab) for children with two subtypes of JIA (poly-JIA and systemic JIA), anti-TNF-α monoclonal antibody (infliximab) for children with Kawasaki disease, and anti-IL-1-ß monoclonal antibody (canakinumab) for children with cryopyrin-associated periodic syndrome. This review summarizes the basis of inflammation in terms of innate immunity and adaptive immunity in these systemic inflammatory diseases, clinical efficacy, and tolerability of these biologic agents, and attempts to determine the roles of individual inflammatory cytokines in disease pathogenesis.

Mycophenolate mofetil as maintenance therapy for childhood-onset systemic lupus erythematosus patients with severe lupus nephritis.

OBJECTIVES: We evaluated histological changes occurring in renal biopsy specimens, between the time before initial induction therapy and after 12 months' maintenance therapy, as well as changes in laboratory parameters, SLE disease activity (SLEDAI), and dosage of corticosteroid (CS) in childhood-onset systemic lupus erythematosus (SLE) patients treated with mycophenolate mofetil (MMF). METHODS: A retrospective analysis was performed on nine patients diagnosed with childhood-onset SLE and lupus nephritis. They were treated with pulsed mPSL and intravenous cyclophosphamide as induction therapy and MMF (500-1500 mg/day) plus CS as maintenance therapy. Renal biopsy was performed before the initial induction therapy and after 12 months' maintenance therapy. RESULTS: Pathological findings at second biopsy were improved in eight of nine patients (89%). The findings of SLEDAI, urinalysis, and blood tests also showed improvement. CS doses could be tapered satisfactorily. Adverse events were observed in two patients. No patients treated with MMF experienced any disease flares during maintenance therapy. CONCLUSIONS: MMF as maintenance therapy might be useful in that not only the histological findings of lupus nephritis were improved, but also CS doses could be beneficially tapered. Nonetheless, this is a retrospective report of only nine cases and further prospective multicenter studies are necessary.

[A case of severe systemic juvenile idiopathic arthritis introduced tocilizumab in early phase of the disease].

A 14-year-old boy was admitted in the former hospital with remittent fever, erythematous rash, joint pain, and muscle pain. Antibiotics were ineffectively administered and then, methylprednisolone (mPSL) pulse therapy with methotrexate was introduced under the diagnosis of suspected systemic juvenile idiopathic arthritis (JIA). However, he still had clinical symptoms and signs, and was transferred to our hospital. Re-examination revealed no malignancies including acute leukemia by bone marrow aspiration, no infectious agents by septic work, and no significant increases of antibodies against several viruses including CMV, EBV, HSV, Parvovirus B19, adenovirus, and so forth. FDG-PET demonstrated the accumulation of (18)F-FDG in bone marrows suggesting systemic JIA. Laboratory findings were leukocytosis and granulocytosis, elevated levels of C-reactive protein, D-dimer, ferritin, and interleukin-6. He was finally diagnosed as having severe systemic JIA. Thus, soon after the additional mPSL pulse therapy, tocilizumab (TCZ) was successfully introduced. In conclusion, for systemic JIA patients with severe systemic inflammation, it will be reasonable to introduce tocilizumab earlier than the guideline suggested to reduce side effects of long-term and large amounts of steroids and to protect the transition to macrophage activation syndrome. Further studies will be needed to recommend appropriate timing of tocilizumab introduction.

Serum levels of anti-SRP54 antibodies reflect disease activity of necrotizing myopathy in a child treated effectively with combinatorial methylprednisolone pulses and plasma exchanges followed by intravenous cyclophosphamide.

We describe the effectiveness of combinatorial therapy with plasma exchanges and methylprednisolone pulses followed by intravenous cyclophosphamide in a young girl with anti-signal recognition particle 54 (SRP54) antibody-associated myopathy. We also use a newly described quantitative assay to demonstrate the close association between the titers of anti-SRP54 antibodies and disease activity. This is the first report of a pediatric patient indicating that the serum levels of anti-SRP54 antibodies are also beneficial for monitoring the disease activity of progressive necrotizing myopathy.

Analysis of gender differences in genetic risk: association of TNFAIP3 polymorphism with male childhood-onset systemic lupus erythematosus in the Japanese population.

BACKGROUND: Systemic lupus erythematosus (SLE) is a systemic multisystem autoimmune disorder influenced by genetic background and environmental factors. Our aim here was to replicate findings of associations between 7 of the implicated single nucleotide polymorphisms (SNPs) in IRF5, BLK, STAT4, TNFAIP3, SPP1, TNIP1 and ETS1 genes with susceptibility to childhood-onset SLE in the Japanese population. In particular, we focused on gender differences in allelic frequencies. METHODOLOGY/PRINCIPAL FINDINGS: The 7 SNPs were genotyped using TaqMan assays in 75 patients with childhood-onset SLE and in 190 healthy controls. The relationship between the cumulative number of risk alleles and SLE manifestations was explored in childhood-onset SLE. Logistic regression was used to test the effect of each polymorphism on susceptibility to SLE, and Wilcoxon rank sum testing was used for comparison of total risk alleles. Data on rs7574865 in the STAT4 gene and rs9138 in SPP1 were replicated for associations with SLE when comparing cases and controls (corrected P values ranging from 0.0043 to 0.027). The rs2230926 allele of TNFAIP3 was associated with susceptibility to SLE in males, but after Bonferroni correction there were no significant associations with any of the other four SNPs in IRF5, BLK, TNIP1 and ETS1 genes. The cumulative number of risk alleles was significantly increased in childhood-onset SLE relative to healthy controls (P = 0.0000041). Male SLE patients had a slightly but significantly higher frequency of the TNFAIP3 (rs2230926G) risk allele than female patients (odds ratio [OR] = 4.05, 95% confidence interval [95%CI] = 1.46-11.2 P<0.05). CONCLUSIONS: Associations of polymorphisms in STAT4 and SPP1 with childhood-onset SLE were confirmed in a Japanese population. Although these are preliminary results for a limited number of cases, TNFAIP3 rs2230926G may be an important predictor of disease onset in males. We also replicated findings that the cumulative number of risk alleles was significantly increased in childhood-onset SLE.

Juvenile fibromyalgia: Guidance for management.

Juvenile fibromyalgia (JFM) is a disease in which patients complain of acute and chronic severe pain, an overt primary cause for which cannot be found or surmised. Although patients with JFM mainly complain of systemic pain or allodynia in the medical interview and physical examination, the concept of the disease is the total sum of painful illness, chronic fatigue, hypothermia and many other autonomic symptoms and signs. Many issues are interacting including individual traits (personality, temperament, sensitivity, memory of pain; age: early adolescence), individual states (self-esteem, anxiety, developmental level), and external stressors (parent especially mother, school environment). JFM is diagnosed on the combination of disease history, physical examination to determine the 18 tender points and allodynia, pain from gently touching their hair, and negative results of blood tests (inflammatory markers, thyroid function, myogenic enzymes). The goals of treatment are the following: restoration of function and relief of pain. Psychological support is advocated. Although the exact number of patients with JFM is still to be elucidated, it seems to be growing because pediatric rheumatologists in Japan encounter children with a wide variety of musculoskeletal pains. This guideline describes how to diagnose JFM in children and how to treat them appropriately.

[Chronic recurrent multifocal osteomyelitis with interstitial myositis].

Chronic recurrent multifocal osteomyelitis (CRMO) is an inflammatory, non-infectious disorder of skeletal system mainly seen in children. We report a case of CRMO presenting with fever and leg pain. The patient was an 11-year-old boy complaining of a fever, swelling and pain on his right foot, and pain on both legs. Although serum levels of CK and aldolase were not increased, MRI imaging suggested polymyositis. Muscle biopsy showed interstitial infiltration of inflammatory cells without any evidences of dermatomyositis or polymyositis. One month later, he complained of a swelling, pain and redness of his left clavicle as recurrently experienced during the recent 6 months, and MRI investigation indicated the diagnosis of osteomyelitis. Bone biopsy was performed and showed chronic inflammatory changes with negative bacterial culture. Multiple bone lesions and muscle uptake of FDG in his legs were revealed by whole body FDG-PET/CT, and he was diagnosed as having CRMO with interstitial myositis. The combinatorial administration of non-steroidal anti-inflammatory drugs and bisphosphonate successfully improved his clinical symptoms and laboratory abnormalities. To our knowledge, there is no report of a patient of CRMO associated with interstitial myositis.