Hiroharu Oki

Danger of frustrated sensors: Role of Toll-like receptors and NOD-like receptors in aseptic and septic inflammations around total hip replacements

Summary The innate immune sensors, Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), can recognize not only exogenous pathogen-associated molecular patterns (PAMPs), but also endogenous molecules created upon tissue injury, sterile inflammation, and degeneration. Endogenous ligands are called damage-associated molecular patterns (DAMPs), and include endogenous molecules released from activated and necrotic cells as well as damaged extracellular matrix. TLRs and NLRs can interact with various ligands derived from PAMPs and DAMPs, leading to activation and/or modulation of intracellular signalling pathways. Intensive research on the innate immune sensors, TLRs and NLRs, has brought new insights into the pathogenesis of not only various infectious and rheumatic diseases, but also aseptic foreign body granuloma and septic inflammation of failed total hip replacements (THRs). In this review, recent knowledge is summarized on the innate immune system, including TLRs and NLRs and their danger signals, with special reference to their possible role in the adverse local host response to THRs. Translational potential of this article: A clear understanding of the roles of Toll-like receptors and NOD-like receptors in aseptic and septic loosening of joint replacements will facilitate potential strategies to mitigate these events, thereby extending the longevity of implants in humans.

AB0381 Expression of Toll-like Receptors and Distribution of Immune-Cells in Rheumatoid Synovial Tissues of The Patients Treated by Abatacept

Background Rheumatoid arthritis (RA) is a progressive chronic autoimmune and autoinflammatory disease affecting multiple joints simultaneously1. Abatacept (ABT) which is cytotoxic T-lymphocyte-associated protein (CTLA) 4-Ig agent is one of biologics2. Objectives The aim of this study is to examine the effect of ABT for evaluating immune-reactive cells with toll-like receptors in the synovial tissue samples of RA patients with ABT therapy (ABT groups) compared to them with non-biological therapy (Non-BIO groups). Methods Synovial tissue samples of 20 RA (10 ABT and 10 Non-BIO samples) were immunohistochemically stained with TLR+ and immune-reactive cells including T cells (CD2), B cells (CD20), macrophage (CD68), conventional dendritic cells (cDC; S100, DC-LAMP), regulatory T cells (FoxP3) and indoleamine 2,3-dioxygenase+ cells (IDO). Positive cells were counted per 10 fields (x 200) by microscopy. TLR positive cells were analyzed by double Immunofluorescent methods with T cell, B cell, macrophage, cDC and plasmacytoid DC (pDC; CD123)-markers and IDO. Synovial inflammation was estimated by Krenn grading score. Results ABT and non-BIO group was shown the similar grading scores (2.3 vs 2.0), DAS28CRP4 (5.1 vs 4.3) and CRP (1.3 vs 0.9). IDO+ and FoxP3+ cells, not CD3+, CD20+ and CD68+ cells were correlated significant with DAS28CRP (4) in lymphoid aggregation in ABT groups (p<0.01). TLR immunoreactivity was also confirmed in pDCs and IDO+ cells by immunofluorescent staining (Fig. 1). Conclusions ABT was reported the similar remarkable effect with other biologics. We have already shown the residual inflammation of synovitis with TLR expressions in the RA patients who were received TNF-blockers3. TLR+ cells were observed with T cells and B cells related local inflammatory grading in ABT groups, however regulatory immune-cells might be increased and regulate inflammatory simultaneously. CTLA-4 and IDO was recently revealed the generation of osteoclast 4,5. IDO+ cells increased in synovial tissues of ABT group compared to no-BIO group. ABT may not only regulate the immunosuppression but also suppress the activation of osteoclast in RA. References Klareskog L, et al: Lancet 2004; 363: 675–681, Sokolove J, ARD, 2015, [Epub ahead of print] Takakubo Y, et al: Clin Rheumatol, 2013; 32: 853–61, Bozec A, et al: SciTranMed, 2014; 7; 235:235ra60 Schiff M, et al: ARD, 2014;73: 2174–7. Acknowledgement We sincerely thank a lot to Ms. Eiko Saito for her skillful technical support in immunohistochemistry. Disclosure of Interest None declared

THU0118 Trend of Atypical Femoral Fractures in Rheumatic Patients in The Highly Super Aging Area of North Japan

Background A number of recent case reports and series have identified atypical fractures of the femoral shaft. Atypical femoral fractures (AFFs) with lack of trauma or less-energy have been reported to relate using of the bisphosphonates (BPs) and glucocorticoids (GCs) for a long time, affecting collagen diseases1,2. Objectives We have analyzed the AFFs in rheumatic patients in the highly super aging area of North Japan, in which the rate more than 65 year-old people in the population was 28%. Methods We investigated retrospectively all cases of AFF summarized by the American Society for Bone and Mineral Research (ASBMR) Task Force 20131 including affected rheumatic disease patients in all hospitals of our prefectural area from 2009 to 2014. Two independent orthpaedic surgeons have diagnosed blindly AFF and estimated proximal femoral geometry by using radiographic analyses. Observation end of this study was settled on Feb 2016. Results We have 86 cases 99 AFFs in our prefectural area from 2009 to 2014 (1.43 cases/100,000 person/year). The rheumatic patients with AFFs were eleven femurs in eight women in that periods and increased year by year (Fig. 1). Three cases have bilateral AFFs (six femurs, 55%). The mean age of them was 54.9 year-old (33–80). As comorbid conditions, five patients have systematic lupus erythematosus, two dermatomyositis and rheumatoid arthritis, one polyarteritis nodosa and systemic sclerosis. Fracture types were seven subtrochanteric and four diaphyseal femoral fractures. Mean femoral neck angle was 133 degrees (120–141) and femoral shaft angle was 6.1 degree (3–10). Six patients with AFF had prodromal pain (55%). All patients received BPs and all but one prednisolone (PSL). Mean duration of receiving those drugs was 52 months (24–120) and 109 months (36–120), respectively. Mean dosage of PSL was 14 mg/day (0–30). In addition, bilateral AFF group has more PSL dose and duration of PSL, more varus deformity of their femur compared to unilateral AFF group (p<0.05). After affecting the fractures, BPs were quitted in seven femurs except four. The surgery using intramedullary nail fixation were performed in all cases excluding one femur using a locking plate. Teriparatide and therapy of low-intensity pulsed ultrasound was induced for five cases after healing their operated wounds. Mean duration of post-operative observation was 28 months (12–70). At the latest follow-up, ten femurs were observed the sign of union at fracture site on X-ray or computed tomography of their femurs, but not one femur. Mean duration of union of the fracture site was 12.6 months (6–24) in ten femurs. Conclusions Eleven AFFs were observed in 2009–14 in rheumatic patients and the numbers were increased year by year in the highly super aging area of North Japan. The careful management and treatment for the AFFs in rheumatic patients are required even after the surgery, because our all cases have been observed the delayed union or non-union of fracture site at their latest follow-up3. In addition, AFF patients who show varus deformity of their femurs and receive much dose of PSL have highly risk of contralateral AFF. References Shane E, et al. JMBR, 2014, Blacks DM, et al. NEJM, 2010, Thompson RN, et al. JBJS, 2012. Acknowledgement We really appreciate all members of Yamagata Prefectural Committee of Atypical Femoral Fractures Study group. Disclosure of Interest None declared

AB0408 Are Atypical Femoral Fractures in Rheumatic Patients Increasing

Background Atypical femoral fractures with low-energy or lack of trauma have been reported to relate using of the bisphosphonates (BPs) and glucocorticoids for a long time, affecting collagen diseases1,2. Objectives The aim of this study was to analyze the atypical femoral fractures in rheumatic patients in our four institutes retrospectively. Methods We investigated the cases of atypical femoral fractures summarized by the American Society for Bone and Mineral Research (ASBMR) Task Force 20101 among our out-rheumatic patients from 2009 to 2014. Results We have 1,091 out-rheumatic patients/year in our four institutes from 2009 to 2014. The patients with atypical femoral fractures were 8 limbs in six women (0.12%) in six years. Three limbs were injured at 2013, and five at 2014, including two cases has both side atypical femoral fractures (Fig. 1). The mean age of them was 51 year-old (38-73). As comorbid conditions, two patients has dermatomyositis, systematic lupus erythematosus, one rheumatoid arthritis and one polyarteritis nodosa. Fracture types were seven subtrochanteric fractures and one diaphyseal femoral fracture. All patients received BPs and prednisolone (PSL). Mean duration of receiving the drugs was 75 months (36-120) and 114 months (60-180), respectively. Mean dosage of PSL was 15 mg/day (5-30). After affecting the fractures, BPs were quitted and the surgery using intramedullary nail fixation were performed in all cases. One case had the surgical-site infection. Teriparatide was induced excepted one case and therapy of low-intensity pulsed ultrasound was started for all cases after healing their operated wounds. Mean duration of post-operative observation was 12 months (5-23). At the latest follow-up, five femurs were observed the sign of union at fracture site on X-ray or computed tomography of their femurs, but not other three femurs. Mean duration of union of the fracture site was 10 months (6-13) in five femurs. Conclusions Eight atypical femoral fractures were observed in 2013-14, but not in 2009-2012. Atypical femoral fracture may increase year by year. The careful management and treatment for the atypical femoral fractures in rheumatic patients were required even after the surgery, because our all cases have been observed the delayed union or non-union of fracture site at their latest follow-up3. References Shane E, et al. JMBR, 2010. Blacks DM, et al. NEJM, 2010. Thompson RN, et al. JBJS 2012. Disclosure of Interest None declared