中村 順一

Abstract Objectives Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. Methods CD4⁺ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. Results Semaphorin 3G expression in CD4⁺ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. Conclusions Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.

OBJECTIVE: Genome-wide association studies (GWAS) have identified >100 risk loci for systemic lupus erythematosus (SLE), but the disease genes at most loci remain unclear, hampering translation of these genetic discoveries. We aimed to prioritise genes underlying the 110 SLE loci that were identified in the latest East Asian GWAS meta-analysis. METHODS: We built gene expression predictive models in blood B cells, CD4+ and CD8+ T cells, monocytes, natural killer cells and peripheral blood cells of 105 Japanese individuals. We performed a transcriptome-wide association study (TWAS) using data from the latest genome-wide association meta-analysis of 208 370 East Asians and searched for candidate genes using TWAS and three data-driven computational approaches. RESULTS: TWAS identified 171 genes for SLE (p<1.0×10-5); 114 (66.7%) showed significance only in a single cell type; 127 (74.3%) were in SLE GWAS loci. TWAS identified a strong association between CD83 and SLE (p<7.7×10-8). Meta-analysis of genetic associations in the existing 208 370 East Asian and additional 1498 cases and 3330 controls found a novel single-variant association at rs72836542 (OR=1.11, p=4.5×10-9) around CD83. For the 110 SLE loci, we identified 276 gene candidates, including 104 genes at recently-identified SLE novel loci. We demonstrated in vitro that putative causal variant rs61759532 exhibited an allele-specific regulatory effect on ACAP1, and that presence of the SLE risk allele decreased ACAP1 expression. CONCLUSIONS: Cell-level TWAS in six types of immune cells complemented SLE gene discovery and guided the identification of novel genetic associations. The gene findings shed biological insights into SLE genetic associations.

<title>Abstract</title> <sec> <title>Introduction</title> Osteonecrosis of the femoral head (ONFH) involves necrosis of bone and bone marrow of the femoral head caused by ischemia with unknown etiology. Previous genetic studies on ONFH failed to produce consistent results, presumably because ONFH has various causes with different genetic backgrounds and the underlying diseases confounded the associations. Steroid-associated ONFH (S-ONFH) accounts for one-half of all ONFH, and systemic lupus erythematosus (SLE) is a representative disease underlying S-ONFH. We performed a genome-wide association study (GWAS) to identify genetic risk factors for S-ONFH in patients with SLE. </sec> <sec> <title>Methods</title> We conducted a two-staged GWAS on 636 SLE patients with S-ONFH and 95 588 non-SLE controls. Among the novel loci identified, we determined S-ONFH specific loci by comparing allele frequencies between SLE patients without S-ONFH and non-SLE controls. We also used Korean datasets comprising 148 S-ONFH cases and 37 015 controls to assess overall significance. We evaluated the functional annotations of significant variants by in-silico analyses. </sec> <sec> <title>Results</title> The Japanese GWAS identified four significant loci together with 12 known SLE susceptibility loci. The four significant variants showed comparable effect sizes on S-ONFH compared with SLE controls and non-SLE controls. Three of the four loci, MIR4293/MIR1265 (OR = 1.99, P-value = 1.1 × 10−9), TRIM49/NAALAD2 (OR = 1.65, P-value = 4.8 × 10−8) and MYO16 (OR = 3.91, P-value = 4.9 × 10−10), showed significant associations in the meta-analysis with Korean datasets. Bioinformatics analyses identified MIR4293, NAALAD2 and MYO16 as candidate causal genes. MIR4293 regulates a PPARG-related adipogenesis pathway relevant to S-ONFH. </sec> <sec> <title>Conclusions</title> We identified three novel susceptibility loci for S-ONFH in SLE. </sec>

Purpose: The Clinical Practice Guidelines for Osteonecrosis of the Femoral Head (ONFH) 2019 Edition, written by the working group for ONFH guidelines of the Japanese Investigation Committee (JIC) for ONFH under the auspices of the Japanese Ministry of Health, Labour, and Welfare and endorsed by the Japanese Orthopaedic Association, were published in Japanese in October 2019. The objective of this guideline is to provide a support tool for decision-making between doctors and patients. Methods: Procedures for developing this guideline were based on the Medical Information Network Distribution Service Handbook for Clinical Practice Guideline Development 2014, which proposed an appropriate method for preparing clinical guidelines in Japan. Results: This clinical practice guideline consists of 7 chapters: epidemiology; pathology; diagnosis; conservative therapy; surgical treatment: bone transplantation/cell therapy; surgical treatment: osteotomy; and surgical treatment: hip replacement. Twelve background questions and 13 clinical questions were determined to define the basic features of the disease and to be addressed when deciding treatment in daily practice, respectively. Conclusions: The clinical practice guidelines for the ONFH 2019 edition will be useful for physicians, investigators, and medical staff in clinical practice, as well as for patients, during the decision-making process when defining how to treat ONFH.

OBJECTIVE: Systemic lupus erythematosus (SLE), an autoimmune disorder, has been associated with nearly 100 susceptibility loci. Nevertheless, these loci only partially explain SLE heritability and their putative causal variants are rarely prioritised, which make challenging to elucidate disease biology. To detect new SLE loci and causal variants, we performed the largest genome-wide meta-analysis for SLE in East Asian populations. METHODS: We newly genotyped 10 029 SLE cases and 180 167 controls and subsequently meta-analysed them jointly with 3348 SLE cases and 14 826 controls from published studies in East Asians. We further applied a Bayesian statistical approach to localise the putative causal variants for SLE associations. RESULTS: We identified 113 genetic regions including 46 novel loci at genome-wide significance (p<5×10-8). Conditional analysis detected 233 association signals within these loci, which suggest widespread allelic heterogeneity. We detected genome-wide associations at six new missense variants. Bayesian statistical fine-mapping analysis prioritised the putative causal variants to a small set of variants (95% credible set size ≤10) for 28 association signals. We identified 110 putative causal variants with posterior probabilities ≥0.1 for 57 SLE loci, among which we prioritised 10 most likely putative causal variants (posterior probability ≥0.8). Linkage disequilibrium score regression detected genetic correlations for SLE with albumin/globulin ratio (rg=-0.242) and non-albumin protein (rg=0.238). CONCLUSION: This study reiterates the power of large-scale genome-wide meta-analysis for novel genetic discovery. These findings shed light on genetic and biological understandings of SLE.

BACKGROUND: The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. METHODS: In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. RESULTS: Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. CONCLUSION: A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

BACKGROUND: Femoral nerve palsy is a serious neurological complication following total hip arthroplasty (THA) via a direct anterior approach. One hypothesis is that the nerve injury is caused by malpositioning of retractors over the anterior wall of the acetabulum. The purpose of this cadaveric study was to clarify the anatomical features of the femoral nerve around the anterior acetabular rim and the potential risk of nerve injury during a direct anterior approach to THA. METHODS: We dissected 84 cadaveric hips from 44 formalin-embalmed cadavers. When the cadavers were supine, the iliopsoas muscle and the femoral nerve were exposed and the anterior joint capsule and labrum were resected. The measurement points were determined along the acetabular rim every 30°, and a reference line was drawn from the anterior superior iliac spine to the center of the acetabulum, with the intersection of the rim at 0°. The minimum distance to the femoral nerve margin was measured from 0° to 150° (6 points). Other anatomical structures were measured to determine their association with the distance of the shortest measurement points. RESULTS: The mean minimum distances to the femoral nerve were 33.2 mm at 0°, 24.4 mm at 30°, 18.4 mm at 60°, 16.6 mm at 90°, 17.9 mm at 120°, and 23.2 mm at 150°, showing that the distance at 90° was the shortest (p < 0.001). The thickness of the iliopsoas muscle and the femoral length were positively associated with the distance to the femoral nerve at 90°. CONCLUSIONS: In this cadaveric study, the femoral nerve was within 16.6 to 33.2 mm of the acetabular rim at points from 0° to 150° of a line drawn from the anterior superior iliac spine. The nerve was closest to the rim at 90°, indicating that this is an area of high risk during retractor placement. CLINICAL RELEVANCE: Retractor placement at 90° to the anterior acetabular rim should be avoided to reduce the risk of femoral nerve injury.

BACKGROUND: The purpose of this prospective cohort study was to clarify the safety and efficacy of total hip arthroplasty via the direct anterior approach in the supine position with a novel mobile traction table. METHODS: The first experience of consecutive surgeries by a single surgeon using the direct anterior approach with a traction table is described with a two-year follow-up period. Of 121 patients, 100 patients without previous hip surgeries, severe deformity, or cemented implants were divided into two groups comprising the first 50 patients and the second 50 patients. RESULTS: The implant survival rate was 99% at the two-year follow-up. Revision surgery was required for periprosthetic femoral fracture in one patient. The complication rate possibly related to the traction table was 5% (5 patients): three anterior dislocations, one periprosthetic femoral fracture, and one intraoperative perforation caused by femoral rasping. The complication rate tended to decrease in the second group compared to the first group (4% versus 6%). Mean surgical time (72.0 minutes versus 82.5 min, p = 0.027), rate of allogeneic blood transfusion (2% versus 24%, p = 0.001), and cup alignment in the safe zone (100% versus 88%, p = 0.027) were significantly improved in the second group compared to the first group. CONCLUSION: The direct anterior approach with a novel mobile traction table showed a positive learning curve for surgical time, rate of allogeneic blood transfusion, and cup alignment in the safe zone.

OBJECTIVES: Our aim was to clarify the distribution of hip pain in patients with osteoarthritis of the hip secondary to developmental dysplasia of the hip (DDH). METHODS: We retrospectively studied 443 hips in 369 patients with osteoarthritis secondary to DDH; mean age was 61 years, and follow-up rate was 84 %. Hip pain was defined as preoperative pain that was relieved 3 months after total hip arthroplasty. RESULTS: Distribution of pain originating in the hip was 89 % (393 hips) to the groin, 38 % (170 hips) to the buttock, 33 % (144 hips) to the anterior thigh, 29 % (130 hips) to the knee, 27 % (118 hips) to the greater trochanter, 17 % (76 hips) to the low back, and 8 % (34 hips) to the lower leg. When the groin, buttock, and greater trochanter were combined as the hip region, 95 % (421 hips) of pain was located in the hip region. On the other hand, when the anterior thigh, knee, lower leg, and low back were combined as the referral region, 55 % (242 hips) showed referred pain. CONCLUSIONS: We suggest that rheumatologists be aware of hip disease masquerading as knee pain or low back pain.

OBJECTIVE: To clarify whether age at the time of the initial administration of corticosteroids is a risk factor for corticosteroid-associated osteonecrosis in children with systemic lupus erythematosus (SLE), using magnetic resonance imaging (MRI). METHODS: From 1986 to 2007, MRI was used to prospectively study 676 joints, including 72 joints (36 hips and 36 knees) in 18 pediatric patients with SLE (<15 years old), 100 joints (50 hips and 50 knees) in 25 adolescent patients with SLE (15-20 years old), and 504 joints (252 hips and 252 knees) in 126 adult patients with SLE (>20 years old), beginning just after corticosteroid administration, for at least 1 year. The followup rate was 100%. RESULTS: In pediatric patients, osteonecrosis developed in 4 joints (6%; all hips). In adolescent patients, osteonecrosis developed in 49 joints (49%; 18 hips and 31 knees). In adult patients, osteonecrosis developed in 207 joints (41%; 95 hips and 112 knees). The rate of osteonecrosis was significantly lower in pediatric patients than in adolescent or adult patients (P = 0.0001). Logistic regression analysis revealed that adolescent and adult patients had a significantly higher risk for osteonecrosis compared with pediatric patients, with an odds ratio of 10.3 (P < 0.0001). The youngest patients with osteonecrosis in the hip and knee were 14.9 years old and 15.5 years old, respectively. Osteonecrosis did not develop in patients younger than age 14 years. CONCLUSION: Our results suggest that age at the time of the initial administration of corticosteroids is associated with osteonecrosis in pediatric patients with SLE.