Yoshihisa Nasu

Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model

OBJECTIVE To investigate the effect of the histone deacetylase (HDAC) inhibitor, trichostatin A (TSA), on joint inflammation and cartilage degeneration in a collagen antibody-induced arthritis (CAIA) mouse model. METHODS CAIA mice were given daily subcutaneous injections of various concentrations of TSA (0, 0.5, 1.0, and 2.0 mg/kg) and various parameters were monitored for 14 days. On Day 15, the hind paws were examined histologically. To investigate the effects of TSA on the expressions of matrix metalloproteinase (MMP)-3, MMP-13, tissue inhibitor of MMP-1 (TIMP-1), and acetyl-H4 by chondrocytes, another group of mice was sacrificed on Day 6. In vitro direct effect of TSA was examined by real-time PCR for mRNA of type II collagen, aggrecan, MMP-3, and MMP-13 in murine chondrogenic ATDC5 cells after pro-inflammatory cytokine stimulation. RESULTS In the TSA-treated group, clinical arthritis was significantly ameliorated in a dose-dependent manner. The severity of synovial inflammation and the cartilage destruction score were significantly lower in the TSA 2.0 mg/kg group compared to the other TSA-treated groups. On immunohistochemistry, the number of MMP-3 and MMP-13-positive chondrocytes was significantly lower in the TSA 2.0 mg/kg group than in the control group. In contrast, the number of TIMP-1-positive cells and acetyl-histone H4-positive cells was significantly higher in the TSA 2.0mg/kg group than in the control group. TSA suppressed interleukin 1-beta and tumor necrosis factor-alpha-stimulated up-regulation of MMP-3, but not MMP-13 mRNA expression by ATDC5. CONCLUSION The systemic administration of TSA ameliorated synovial inflammation in CAIA mice. Subsequently cartilage destruction was also suppressed by TSA, at least in part, by modulating chondrocyte gene expression.

Intra-articular injection of interleukin-4 decreases nitric oxide production by chondrocytes and ameliorates subsequent destruction of cartilage in instability-induced osteoarthritis in rat knee joints

OBJECTIVE To investigate the in vitro and in vivo effects of interleukin (IL)-4 on mechanical stress-induced nitric oxide (NO) expression by chondrocytes, and destruction of cartilage and NO production in an instability-induced osteoarthritis (OA) model in rat knee joints, respectively. MATERIALS AND METHODS Cyclic tensile stress (CTS; 0.5Hz and 7% elongation) was applied to cultured normal rat chondrocytes with or without pre-incubation with recombinant rat IL-4 (rrIL-4). Inducible NO synthase (iNOS) mRNA expression and NO production were examined with real-time polymerase chain reaction and the Griess reaction, respectively. OA was induced in rat knee joints by transection of the anterior cruciate and medial collateral ligaments and resection of the medial meniscus. rrIL-4 (10, 50, and 100 ng/joint/day) was injected intra-articularly, and knee joint samples were collected 2, 4, and 6 weeks after surgery. Cartilage destruction was evaluated by the modified Mankin score and Osteoarthritis Research Society International scoring system on paraffin-embedded sections stained with safranin O. Cleavage of aggrecan and NO production were examined by immunohistochemistry for aggrecan neoepitope (NITEGE) and of nitrotyrosine (NT), respectively. RESULTS rrIL-4 down-regulated CTS-induced iNOS mRNA expression and NO production by chondrocytes. The intra-articular injection of rrIL-4 gave rise to a limited, but significant amelioration of cartilage destruction, prevention of loss of aggrecan, and decrease in the number of NT-positive chondrocytes, an effect that was not dose-dependent. CONCLUSION The present study suggests that IL-4 may exert chondroprotective properties against mechanical stress-induced cartilage destruction, at least in part, by inhibiting NO production by chondrocytes.

Abatacept management during the perioperative period in patients with rheumatoid arthritis: report on eight orthopaedic procedures

1 Department of Human Morphology, Science of Functional Recovery and Reconstruction, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, 2 Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan, and 3 Department of Orthopaedic Surgery, Kurashiki Sweet Hospital, Kurashiki City, Okayama, Japan

Risk factors for surgical site infection and delayed wound healing after orthopedic surgery in rheumatoid arthritis patients

Abstract Objective: To investigate the prevalence and the risk factors of surgical-site infection (SSI) and delayed wound healing (DWH) in patients with rheumatoid arthritis (RA) underwent orthopedic surgery. Methods: We reviewed the records of 1036 elective orthopedic procedures undertaken in RA patients. Risk factors for SSI and DWH were assessed by logistic regression analysis using age, body mass index, disease duration, pre-operative laboratory data, surgical procedure, corticosteroid use, co-morbidity, and use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) and biological DMARDs (bDMARDs) as variables. Results: SSI and DWH were identified in 19 cases and 15 cases, respectively. One case of SSI and three cases of DWH were recorded among 196 procedures in patients using bDMARDs. Foot and ankle surgery was associated with an increased risk of SSI (odds ratio (OR), 3.167; 95% confidence interval (CI), 1.256–7.986; p = 0.015). Total knee arthroplasty (TKA; OR, 4.044; 95% CI, 1.436–11.389; p = 0.008) and disease duration (OR, 1.004; 95% CI, 1.000–1.007; p = 0.029) were associated with an increased risk of DWH. Conclusions: Our results indicated foot and ankle surgery, and TKA and disease duration as risk factors for SSI and DWH, respectively. bDMARDs was not associated with an increased risk of SSI and DWH.

The clinical course of patients with rheumatoid arthritis who underwent orthopaedic surgeries under disease control by tofacitinib

Keiichiro Nishida, Ryozo Harada, Yoshihisa Nasu, Ayumu Takeshita, Ryuichi Nakahara, Masamitsu Natsumeda and Toshifumi Ozaki Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences, Okayama, Japan; Department of Orthopaedic Surgery, Kurashiki Sweet Hospital, Okayama, Japan; Department of Medical Materials for Musculoskeletal Reconstruction, Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences, Okayama, Japan; Department of Musculoskeletal Traumatology, Okayama University Graduate School of Medicine, Density and Pharmaceutical Sciences, Okayama, Japan; Mabi Memorial Hospital Rheumatic Disease Center, Kurashiki, Japan

Short-term results of the PROSNAP linked elbow prosthesis with a snap-in structure and modular flange for the reconstruction of severely damaged rheumatoid elbows

BACKGROUND We aimed to evaluate the early clinical results of the reconstruction of problematic elbow joints due to rheumatoid arthritis (RA) using a PROSNAP linked elbow prosthesis (Kyocera Medical, Osaka, Japan) for total elbow arthroplasty. METHODS Seventeen elbows in 14 RA patients were replaced with a PROSNAP elbow with cement fixation. The patients comprised 1 man and 13 women, with a mean age of 63.9 years (range, 52-83 years) at the time of surgery. The preoperative conditions of the elbows were arthritis mutilans (n = 10), an ankylosed or stiff elbow with a preoperative range of motion of 45° or less (n = 4), and loosening of a primary total elbow arthroplasty (n = 3). The mean follow-up period was 47.7 months (range, 32-69 months), with a 100% follow-up rate. The clinical outcome of the elbows was evaluated by the Mayo Elbow Performance Index (maximum, 100 points). RESULTS The mean postoperative Mayo Elbow Performance Index score improved from 57.6 points to 97.1 points. Preoperatively, 3 of the 17 elbows were judged as good, 7 as fair, and 7 as poor; at final follow-up, 16 elbows were judged as excellent and 1 as good. Complications were noted in 1 elbow (6%), which had undergone a postoperative fracture. CONCLUSIONS The PROSNAP elbow prosthesis can be safely implanted through a relatively easy procedure and provides satisfactory short-term clinical outcomes for the reconstruction of severely damaged RA elbows. LEVEL OF EVIDENCE Level IV, case series, treatment study.

Mid-term results of alumina ceramic unlinked total elbow arthroplasty with cement fixation for patients with rheumatoid arthritis

Aims The aim of this study was to report the mid‐term clinical outcome of cemented unlinked J‐alumina ceramic elbow (JACE) arthroplasties when used in patients with rheumatoid arthritis (RA). Patients and Methods We retrospectively reviewed 87 elbows, in 75 patients with RA, which was replaced using a cemented JACE total elbow arthroplasty (TEA) between August 2003 and December 2012, with a follow‐up of 96%. There were 72 women and three men, with a mean age of 62 years (35 to 79). The mean follow‐up was nine years (2 to 14). The clinical condition of each elbow before and after surgery was assessed using the Mayo Elbow Performance Index (MEPI, 0 to 100 points). Radiographic loosening was defined as a progressive radiolucent line of >1 mm that was completely circumferential around the prosthesis. Results The mean MEPI scores significantly improved from 40 (10 to 75) points preoperatively to 95 (30 to 100) points at final follow‐up (p < 0.0001). Complications were noted in ten elbows (ten patients; 11%). Two had an intraoperative humeral fracture which was treated by fixation and united. One had a postoperative fracture of the olecranon which united with conservative treatment and one had a radial neuropathy which resolved. Further surgery was required for one with a dislocation, three with an ulnar neuropathy and one with a postoperative humeral fracture. Revision with removal of the components was performed in one elbow due to deep infection. There was no radiographic evidence of loosening around the components.With any revision surgery or revision with implant removal as the endpoint, the rates of survival up to 14 years were 93% (95% confidence interval (CI), 83.9 to 96.6) and 99% (95% CI 91.9 to 99.8), respectively, as determined by Kaplan‐Meier analysis. Conclusion With the appropriate indications, the mid‐term clinical performance of the cemented JACE TEA is reliable and comparable to other established TEAs in the management of the elbow in patients with RA. Cite this article: Bone Joint J 2018;100‐B:1066–73.

Outcomes of Resection and Joint-Preserving Arthroplasty for Forefoot Deformities for Rheumatoid Arthritis

Background: We investigated the clinical outcomes of resection and joint-preserving arthroplasty for forefoot deformities in patients with rheumatoid arthritis. Methods: Sixteen feet of 14 women (average age, 67.1 years; range, 53-82) underwent resection arthroplasty of the metatarsal head (resection group), and 18 feet of 15 women (average age, 61.3 years; range, 40-73) underwent a metatarsophalangeal joint-preserving procedure with shortening oblique metatarsal osteotomies of the lesser toes (joint preservation group). The mean disease duration in the resection and joint preservation groups was 23.6 and 19.1 years, and the average follow-up period was 37.3 and 33.5 months, respectively. The classification of Larsen was used to assess the severity of destruction of the metatarsophalangeal (MTP) joint. Preoperative and postoperative clinical evaluation included Japanese Society for Surgery of the Foot (JSSF) score and postoperative complications. Results: The number of preoperative radiographic destruction of the MTP joints (Larsen grade II, III, IV, and V) was 0, 29, 39, and 12 joints in the resection group and 13, 67, 9, and 1 joints in the joint preservation group. The mean JSSF score improved significantly from 61.3 to 83.9 points in the resection group (P < .001) and from 62.2 to 90.8 points in the joint preservation group (P < .001). In the resection group, recurrence of callosities and claw toe deformity was observed in 6 and 3 feet, respectively. In the joint-preserving group, recurrence of callosities and hammer toe deformity was observed in 1 foot each. Conclusion: The resection arthroplasty and joint-preserving procedure showed satisfactory clinical outcomes. However, whether both procedures can maintain the good clinical results without the recurrence of forefoot deformity will require longer follow-up. Level of Evidence: Level III, retrospective comparative series.

Dramatic Effect of Tofacitinib on TNF-Inhibitor Resistant Synovitis: A Case Report

A 58-year-old woman with a 2.5-year history of rheumatoid arthritis showed a pain, severe swelling, and a decreased range of motion of left knee joint. Medical therapy with 8 mg per week of oral methotrexate and 1 mg per day of tacrolimus in combination with 40 mg per 2 weeks of adalimumab failed to control the disease activity. Administration of tofacitinib achieved the successful disease control, and MRI taken 5 months after the initiation of tofacitinib showed the disappearance of synovial mass within the knee joint and the bone marrow oedema and marked reduction of the popliteal cyst. The use of tofacitinib for inadequate response to the first TNF inhibitor as a third-line DMARD showed dramatic effect on severe synovitis, and the patient could avoid the surgical intervention.

AB0177 Patient-Reported Outcome of Upper Extremity Surgery for Rheumatoid Arthritis

Background The goal of treat to target (T2T) is the clinical remission in patients with early disease, but it is difficult to achieve the functional remission. Although patients subjective evaluation is important for the assessment of postoperative functions of rheumatoid arthritis (RA) patients, there are few reports examined the patients-reported functions after upper extremity surgery for RA. Objectives Between 2011 and 2014, 158 RA patients underwent the surgical treatment on upper extremities, and all patients were available for detailed clinical review over a 1-year follow-up period. There were 144 females and 14 males with a mean age at surgery of 59.7 (range, 18–85) years. The average disease duration at the surgery was 19.6 (range, 1–59) years. Methods The clinical outcome of the surgery was assessed by the disease activity (DAS28-CRP), Health Assessment Questionnaire Disability Index (HAQ-DI), Disability of Arm Shoulder and Hand (DASH), Hand20 questionnaire (Hand20). The patients were divided by surgical site into 3 groups (elbow, wrist and finger groups) and by the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) into 2 groups (bDMARDs and non-bDMARDs groups) to compare and evaluate the outcomes. Results The mean of preoperative/postoperative DAS28-CRP, HAQ-DI, DASH and Hand20 were 2.9/2.3, 0.88/0.94, 46.4/39.1 and 59.1/47.6, respectively. All outcomes except for HAQ-DI significantly improved after the surgery. All outcomes improved significantly in the elbow group, but could not reach significant improvement in the finger group. We further examined the postoperative change in each items of DASH and Hand20, and found the significant improvements in items about pain and weakness in elbow group, pain and rotation of forearm in wrist group, and delicate movement and cosmetic factor in finger group. Postoperative DASH and Hand20 scores were tend to improve in the both bDMARDs and non-bDMARDs group. Conclusions Our results confirmed the surgery on upper extremity of RA improved the patients reported function, as well as the disease activity. There were surgical site-specific pattern of improvement of DASH and Hand20, such as that gross movement and pain significantly improved in larger joints, and dexterity movement and cosmetic factor in smaller joints. Postoperative upper extremity function was tend to improve, but more significantly in non-bDMARDs group, probably because the patients might had relatively better baseline function in the bDMARDs group. Understanding of site-specific patterns of improvement after surgery might be useful to achieve the functional remission, and may contribute to decision making of surgical indication, priority of surgical site on upper extremity, and prospection of surgical outcome. References Moromoto H, et al. Reliability of the Hand20 questionnaire: comparison with the 36-Item Short-Form Health Survey. Hand Surg. 2014;19(1):1–6 Hudak PL, et al. Development of an upper extremity outcome measure: the DASH (disabilities of the arm, shoulder and hand) [corrected]. The Upper Extremity Collaborative Group (UECG). Am J Ind Med. 1996 Jun;29(6):602–8. Disclosure of Interest None declared