Toshimasa Shimizu

Dysregulated mature IL-1β production in familial Mediterranean fever

OBJECTIVE The aim of this study was to analyse the role of circulating cleaved IL-1β in patients with FMF. METHODS We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1β was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1β antibody. RESULTS Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1β (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1β were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1β (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase. CONCLUSION The cleaved form of IL-1β is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1β-mediated inflammatory disorders.

A long-term follow-up of Japanese mother and her daughter with Blau syndrome: Effective treatment of anti-TNF inhibitors and useful diagnostic tool of joint ultrasound examination

Blau syndrome (BS) is an autosomal dominant autoinflammatory disease associated with NOD2 gene mutations. It is characterized by arthritis, skin rash, and uveitis. Here, we report contrasting outcomes of a daughter and her mother with BS. Their long-term follow-up revealed the efficacy of anti-tumor necrosis factor inhibitor (TNF) with respect to BS. Joint findings of BS feature tenosynovitis over articular synovitis on ultrasonography. BS might be one of the differential diagnoses of juvenile idiopathic arthritis and rheumatoid arthritis.

Magnetic Resonance Imaging Bone Edema at Enrollment Predicts Rapid Radiographic Progression in Patients with Early RA: Results from the Nagasaki University Early Arthritis Cohort.

Objective. To clarify whether magnetic resonance imaging (MRI) bone edema predicts the development of rapid radiographic progression (RRP) in the Nagasaki University Early Arthritis Cohort of patients with early-stage rheumatoid arthritis (RA). Methods. Patients with early-stage RA (n = 76) were enrolled and underwent 1.5-T MRI of both wrists and finger joints. Synovitis, bone edema, and bone erosion were evaluated using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS). RRP was defined as an annual increment > 3 at 1 year by the Genant-modified Sharp score of plain radiographs. A multivariate logistic regression analysis was performed to establish the risk factors for RRP. Results. Median disease duration at enrollment was 3 months. RRP was found in 12 of the 76 patients at 1 year. A univariate analysis revealed that matrix metalloprotease-3, RAMRIS bone edema score, and RAMRIS bone erosion score were associated with RRP. Multivariate logistic regression analyses demonstrated that the RAMRIS bone edema score at enrollment (5-point increase, OR 2.18, 95% CI 1.32–3.59, p = 0.002) was the only independent predictor of the development of RRP at 1 year. A receiver-operating characteristic analysis identified the best cutoff value for RAMRIS bone edema score as 5. RRP was significantly rare among the patients with a RAMRIS bone edema score < 5 at enrollment (2 from 50 patients). Conclusion. Our findings suggest that MRI bone edema is closely associated with the development of RRP in patients with early-stage RA. Physicians should carefully control the disease activity when MRI bone edema is observed in patients with early RA.

Increased prevalence of MEFV exon 10 variants in Japanese patients with adult-onset Still's disease.

Autoinflammatory diseases include a large spectrum of monogenic diseases, e.g. familial Mediterranean fever (FMF), as well as complex genetic trait diseases, e.g. adult‐onset Stills disease (AOSD). In populations where FMF is common, an increased MEFV mutation rate is found in patients with rheumatic diseases. The aim of this study was to examine MEFV mutations in Japanese patients with AOSD. Genomic DNA was isolated from 49 AOSD patients and 105 healthy controls, and exons 1, 2, 3 and 10 of the MEFV gene genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. We found no significant difference in overall allele frequencies of MEFV variants between AOSD patients and controls. However, MEFV exon 10 variants (M694I and G632S) were significantly higher in AOSD patients than controls (6·1 versus 0%). In addition, there was no significant difference between MEFV variant carriers and non‐carriers with clinical manifestations, but the monocyclic clinical course of the AOSD disease phenotype was observed less frequently in patients without MEFV variants. AOSD patients had significantly higher frequencies of MEFV exon 10 mutations, suggesting that low‐frequency variants of MEFV gene may be one of the susceptibility factors of AOSD.

Soluble α-klotho is a potential biomarker associated with neuropsychiatric systemic lupus erythematosus.

A reduced level of the single-pass transmembrane protein α-Klotho is known to be associated with neuronal damage. We investigated whether α-Klotho in cerebrospinal fluid (CSF) could be a candidate marker for the diagnosis of neuropsychiatric systemic lupus erythematosus (NPSLE). We analyzed the laboratory data, symptoms and radiological image findings of 34 NPSLE patients. Patients with SLE without neuropsychiatric manifestations (SLE) (n=25), and patients with viral meningitis (VM) (n=19), multiple sclerosis (MS) (n=20) or neuromyelitis optica (NMO) (n=20) were included as controls. The multivariable analyses revealed that lower CSF α-Klotho level, lower serum anti-Smith antibodies (U/mL) and higher serum C3 (mg/dL) were significant factors for predicting NPSLE. The CSF α-Klotho levels of the NPSLE patients were inversely correlated with the level of granulocyte/macrophage-colony stimulating factor. Our data suggested that the determination of CSF α-Klotho levels will contribute to the diagnosis of NPSLE and help elucidate the mechanisms underlying this disease.

M1 and M2 Monocytes in Rheumatoid Arthritis: A Contribution of Imbalance of M1/M2 Monocytes to Osteoclastogenesis

Objectives We investigated the relationships among M1 monocytes, M2 monocytes, osteoclast (OC) differentiation ability, and clinical characteristics in patients with rheumatoid arthritis (RA). Methods Peripheral blood mononuclear cells (PBMCs) were isolated from RA patients and healthy donors, and we then investigated the number of M1 monocytes or M2 monocytes by fluorescence-activated cell sorting. We also obtained and cultured CD14-positive cells from PBMCs from RA patients and healthy donors to investigate OC differentiation in vitro. Results Forty RA patients and 20 healthy donors were included. Twenty-two patients (55%) were anticitrullinated protein antibody (ACPA) positive. The median M1/M2 ratio was 0.59 (0.31–1.11, interquartile range). There were no significant differences between the RA patients and healthy donors. There was a positive correlation between the M1/M2 ratio and the differentiated OC number in vitro in RA patients (ρ = 0.81, p < 0.001). The ACPA-positive patients had significantly higher M1/M2 ratios in vivo (p = 0.028) and significantly greater numbers of OCs in vitro (p = 0.005) than the ACPA-negative patients. Multivariable regression analysis revealed that the M1/M2 ratio was the sole significant contribution factor to in vitro osteoclastogenesis. RA patients with M1/M2 ratios >1 (having relatively more M1 monocytes) had higher C-reactive protein and erythrocyte sedimentation rates than RA patients with M1/M2 ratios ≤1. M1-dominant monocytes in vitro produced higher concentrations of interleukin-6 upon stimulation with lipopolysaccharide than M2 monocytes. Conclusion M1/M2 monocytes imbalance strongly contributes to osteoclastogenesis of RA patients. Our findings cast M1 and M2 monocyte subsets in a new light as a new target of treatments for RA to prevent progression of osteoclastic bone destruction.

Ultrasound-detected bone erosion is a relapse risk factor after discontinuation of biologic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis whose ultrasound power Doppler synovitis activity and clinical disease activity are well controlled

BackgroundIn the present study, we explored the risk factors for relapse after discontinuation of biologic disease-modifying antirheumatic drug (bDMARD) therapy in patients with rheumatoid arthritis (RA) whose ultrasound power Doppler (PD) synovitis activity and clinical disease activity were well controlled.MethodsIn this observational study in clinical practice, the inclusion criteria were based on ultrasound disease activity and clinical disease activity, set as low or remission (Disease Activity Score in 28 joints based on erythrocyte sedimentation rate <3.2). Ultrasound was performed in 22 joints of bilateral hands at discontinuation for evaluating synovitis severity and presence of bone erosion. Patients with a maximum PD score ≤1 in each joint were enrolled. Forty patients with RA were consecutively recruited (November 2010–March 2015) and discontinued bDMARD therapy. Variables at the initiation and discontinuation of bDMARD therapy that were predictive of relapse during the 12 months after discontinuation were assessed.ResultsThe median patient age was 54.5 years, and the median disease duration was 3.5 years. Nineteen (47.5%) patients relapsed during the 12 months after the discontinuation of bDMARD therapy. Logistic regression analysis revealed that only the presence of bone erosion detected by ultrasound at discontinuation was predictive of relapse (OR 8.35, 95% CI 1.78–53.2, p = 0.006). No clinical characteristics or serologic biomarkers were significantly different between the relapse and nonrelapse patients. The ultrasound synovitis scores did not differ significantly between the groups.ConclusionsOur findings are the first evidence that ultrasound bone erosion may be a relapse risk factor after the discontinuation of bDMARD therapy in patients with RA whose PD synovitis activity and clinical disease activity are well controlled.

Efficacy and safety at 24 weeks of daily clinical use of tofacitinib in patients with rheumatoid arthritis

Objective We evaluated the efficacy and safety of tofacitinib in patients with rheumatoid arthritis (RA) in a real-world setting. Methods Seventy consecutive patients, for whom tofacitinib was initiated between November 2013 and May 2016, were enrolled. All patients fulfilled the 2010 ACR/EULAR classification criteria for RA. All patients received 5 mg of tofacitinib twice daily and were followed for 24 weeks. Clinical disease activity indicated by disease activity score (DAS)28-ESR, the simplified disease activity index, and the clinical disease activity index as well as adverse events (AEs) were evaluated. Statistical analysis was performed to determine which baseline variables influenced the efficacy of tofacitinib at 24 weeks. Results Fifty-eight patients (82.9%) continued tofacitinib at 24 weeks. Clinical disease activity rapidly and significantly decreased, and this efficacy continued throughout the 24 weeks: i.e., DAS28-ESR decreased from 5.04 ± 1.33 at baseline to 3.83 ± 1.11 at 4 weeks and 3.53 ± 1.17 at 24 weeks (P<0.0001, vs. baseline). 15 AEs including 5 herpes zoster infection occurred during tofacitinib treatment. The efficacy of tofacitinib was not changed in patients without concomitant use of methotrexate (MTX) or patients whose treatment with tocilizumab (TCZ) failed. Multivariable logistic analysis showed that the number of biologic DMARDs (bDMARDs) previously used was independently associated with achievement of DAS-low disease activity. Conclusions Our present study suggests that tofacitinib is effective in real-world settings even without concomitant MTX use or after switching from TCZ. Our results also suggest that its efficacy diminishes if started after use of multiple bDMARDs.

Effects of HLA-DRB1 alleles on susceptibility and clinical manifestations in Japanese patients with adult onset Still’s disease

BackgroundHLA-DRB1 alleles are major determinants of genetic predisposition to rheumatic diseases. We assessed whether DRB1 alleles are associated with susceptibility to particular clinical features of adult onset Still’s disease (AOSD) in a Japanese population by determining the DRB1 allele distributions.MethodsDRB1 genotyping of 96 patients with AOSD and 1,026 healthy controls was performed. Genomic DNA samples from the AOSD patients were also genotyped for MEFV exons 1, 2, 3, and 10 by direct sequencing.ResultsIn Japanese patients with AOSD, we observed a predisposing association of DRB1*15:01 (p = 8.60 × 10−6, corrected p (Pc) = 0.0002, odds ratio (OR) = 3.04, 95% confidence interval (95% CI) = 1.91–4.84) and DR5 serological group (p = 0.0006, OR = 2.39, 95% CI = 1.49–3.83) and a protective association of DRB1*09:01 (p = 0.0004, Pc = 0.0110, OR = 0.34, 95% CI = 0.18–0.66) with AOSD, and amino acid residues 86 and 98 of the DRβ chain were protectively associated with AOSD. MEFV variants were identified in 49 patients with AOSD (56.3%). The predisposing effect of DR5 was confirmed only in patients with AOSD who had MEFV variants and not in those without MEFV variants. Additionally, DR5 in patients with AOSD are associated with macrophage activation syndrome (MAS) and steroid pulse therapy.ConclusionThe DRB1*15:01 and DR5 are both associated with AOSD susceptibility in Japanese subjects. A protective association between the DRB1*09:01 allele and AOSD was also observed in these patients. Our data also highlight the effects of DRB1 alleles in susceptibility to AOSD.

Synovitis of sternoclavicular and peripheral joints can be detected by ultrasound in patients with SAPHO syndrome.

Abstract Objectives: To determine the prevalence of ultrasonographic abnormalities of sternoclavicular joints (SCJ) and peripheral joints (PJ) in patients with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome. Methods: Thirteen patients with SAPHO syndrome who fulfilled diagnostic criteria proposed by Kahn for SAPHO syndrome 2003 and 13 healthy individuals age- and sex-matched were enrolled. Synovitis, defined by synovial hypertrophy with power Doppler (PD) signals, of the SCJ and the PJ including wrist, MCP, PIP, and the other symptomatic joints were evaluated by ultrasound (US). Results: Synovitis with PD signals was detected in 16 (61.5%) of the 26 SCJ and 11 (84.6%) of the SAPHO syndrome patients, and none of the controls. Synovitis with PD signals in any PJ was detected in 4 (30.7%) of the SAPHO syndrome patients. Conclusions: Synovitis of the SCJ and PJ in SAPHO syndrome was detectable by US with a PD method. US can be useful for the diagnosis of SAPHO syndrome.