sCD28, sCD80, sCTLA-4, and sBTLA Are Promising Markers in Diagnostic and Therapeutic Approaches for Aseptic Loosening and Periprosthetic Joint Infection

Aseptic prosthetic loosening and periprosthetic joint infections (PJI) are among the most frequent complications after total knee/hip joint arthroplasty (TJA). Current research efforts focus on understanding the involvement of the immune system in these frequent complications. Different immune cell types have already been implicated in aseptic prosthetic loosening and PJI. The aim of this study was to systematically analyze aspirates from knee and hip joints, evaluating the qualitative and quantitative composition of soluble immunoregulatory markers, with a focus on co-inhibitory and co-stimulatory markers. It has been shown that these molecules play important roles in immune regulation in cancer and chronic infectious diseases, but they have not been investigated in the context of joint replacement. For this purpose, aspirates from control joints (i.e., native joints without implanted prostheses), joints with TJA (no signs of infection or aseptic loosening), joints with aseptic implant failure (AIF; i.e., aseptic loosening), and joints with PJI were collected. Fourteen soluble immunoregulatory markers were assessed using bead-based multiplex assays. In this study, it could be shown that the concentrations of the analyzed immunoregulatory molecules vary between control, TJA, AIF, and PJI joints. Comparing TJA patients to CO patients, sCD80 was significantly elevated. The marker sBTLA was significantly elevated in AIF joints compared to TJA joints. In addition, a significant difference for eight markers could be shown when comparing the AIF and CO groups (sCD27, sCTLA-4, sCD137, sCD80, sCD28, sTIM-3, sPD-1, sBTLA). A significant difference was also reached for nine soluble markers when the PJI and CO groups were compared (sLAG-3, sCTLA-4, sCD27, sCD80, sCD28, sTIM-3, sPD-1, IDO, sBTLA). In summary, the analyzed immunoregulatory markers could be useful for diagnostic purposes as well as to develop new therapeutic approaches for AIF and PJI.

A Comparative Study of Total Knee Arthroplasty Outcome for Stiff Knee with or without Sequential Antirheumatic Drug Treatment

BackgroundTo evaluate influence of antirheumatic drug treatment on knee function of patients with stiff knee after total knee arthroplasty (TKA). MethodsTwenty-seven patients (44 knees) of active RA (rheumatoid arthritis) or AS (ankylosing spondylitis) with stiff knee were included in this study. And they were divided into two groups according to continue antirheumatic drug treatment or not after TKA: the therapeutic group (16 patients, 27 knees) and the controlled group (11 patients, 17 knees). The outcomes were assessed by Knee Society Score (KSS), Visual Analogue Scale (VAS), range of motion (ROM) (at week 6, month 6, year 1 and year 2), “Forgotten Joint” Scale (FJS), with or without crutch, satisfaction and revision (at year 2). The knee prosthetic loosening was evaluated by the followed X-ray at each following time. ResultsThe mean follow-up time was 51 months (34-69 months). The KSS were higher at week 6 after TKA in the therapeutic group (p < 0.05), however, the functional scores of KSS at month 6, year 1 and year 2 in the controlled group were more points improved. The therapeutic patients preferred the knee more at month 6, year 1 and year 2. The differences of KSS clinical scores (at month 6, year 1 and year 2), VAS, ROM, Crutch and FJS between the two groups were not statistically significant (p＞0.05). ConclusionFor patients with stiff knees, the sequential antirheumatic drug treatment after TKA had no effect on postoperative KSS, but can improve the satisfaction.Level of evidenceTherapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Celastrol Attenuates RANKL-Induced Osteoclastogenesis in vitro and Reduces Titanium Particle-Induced Osteolysis and Ovariectomy-Induced Bone Loss in vivo

Excessive bone resorption by osteoclasts contributes significantly to osteoclast-related diseases such as periprosthetic osteolysis and osteoporosis. Osteolysis in a titanium particle-induced calvarial model and bone loss in an ovariectomized mice model occurred similarly to those in humans; thus, these models can be used to evaluate potential therapies for aseptic prosthetic loosening and osteoporosis. Celastrol, which is extracted from the seeds of the genus Tripterygium, has been thoroughly investigated for its anti-inflammatory and anti-cancer pharmacological effects. However, the mechanisms involving bone metabolism by which celastrol inhibits osteoclastogenesis are not yet fully understood. We demonstrated that celastrol inhibited the receptor activator of nuclear factor κB ligand-induced osteoclastogenesis and the bone resorptive function of osteoclasts in vitro by inhibiting the activation of transforming growth factor β-activated kinase 1-mediated NF-κB and mitogen-activated protein kinase signaling pathways and downregulating osteoclastogenesis marker-related genes. Furthermore, celastrol was also shown to be beneficial in both the titanium particle-induced osteolysis calvarial and the murine ovariectomy-induced bone loss. Collectively, our results suggested that celastrol is promising for the prevention of aseptic prosthetic loosening and osteoporosis in the treatment of osteolytic diseases induced by disrupted osteoclast formation and function.

Should all hip and knee prosthetic joints be aspirated prior to revision surgery?

Aims It is essential to exclude a periprosthetic joint infection (PJI) prior to revision surgery. It is recommended to routinely aspirate the joint before surgery. However, this may not be necessary in a subgroup of patients. The aim of our study was to investigate if specific clinical and implant characteristics could be identified to rule out a PJI prior to revision surgery. Methods We retrospectively evaluated clinical and implant characteristics of patients who underwent a hip or knee revision surgery between October 2015 and October 2018. Patients were diagnosed with a PJI according to the MSIS diagnostic criteria. Results A total of 156 patients were analyzed, including 107 implants that were revised because of prosthetic loosening and 49 because of mechanical failure (i.e. instability, malalignment or malpositioning). No PJI was diagnosed in the group with mechanical failure. In the prosthetic loosening group, 20 of 107 were diagnosed with a PJI (19%). Although there was a significantly lower chance of having a PJI with an implant age of > 5 years combined with a CRP < 5 mg/L, an infection was still present in 3 out of 39 cases (8%). Conclusion Implants with solely mechanical failure without signs of loosening and low inflammatory parameters probably do not require a synovial fluid aspiration. These results need to be confirmed in a larger cohort of patients. In case of prosthetic loosening, all joints need to be aspirated before surgery as no specific characteristic could be identified to rule out an infection.

The Effect of Inflammation on Bone

Bone remodeling is the continual process to renew the adult skeleton through the sequential action of osteoblasts and osteoclasts. Nuclear factor RANK, an osteoclast receptor, and its ligand RANKL, expressed on the surface of osteoblasts, result in coordinated control of bone remodeling. Inflammation, a feature of illness and injury, plays a distinct role in skewing this process toward resorption. It does so via the interaction of inflammatory mediators and their related peptides with osteoblasts and osteoclasts, as well as other immune cells, to alter the expression of RANK and RANKL. Such chemical mediators include TNFα, glucocorticoids, histamine, bradykinin, PGE2, systemic RANKL from immune cells, and interleukins 1 and 6. Conditions, such as periodontal disease and alveolar bone erosion, aseptic prosthetic loosening, rheumatoid arthritis, and some sports related injuries are characterized by the result of this process. A thorough understanding of bone response to injury and disease, and ability to detect such biomarkers, as well as imaging to identify early structural and mechanical property changes in bone architecture, is important in improving management and outcomes of bone related pathology. While gut health and vitamin and mineral availability appear vitally important, nutraceuticals also have an impact on bone health. To date most pharmaceutical intervention targets inflammatory cytokines, although strategies to favorably alter inflammation induced bone pathology are currently limited. Further research is required in this field to advance early detection and treatments.

Incremental inputs improve the automated detection of implant loosening using machine-learning algorithms

Aims The aim of this study was to evaluate the ability of a machine-learning algorithm to diagnose prosthetic loosening from preoperative radiographs and to investigate the inputs that might improve its performance. Methods A group of 697 patients underwent a first-time revision of a total hip (THA) or total knee arthroplasty (TKA) at our institution between 2012 and 2018. Preoperative anteroposterior (AP) and lateral radiographs, and historical and comorbidity information were collected from their electronic records. Each patient was defined as having loose or fixed components based on the operation notes. We trained a series of convolutional neural network (CNN) models to predict a diagnosis of loosening at the time of surgery from the preoperative radiographs. We then added historical data about the patients to the best performing model to create a final model and tested it on an independent dataset. Results The convolutional neural network we built performed well when detecting loosening from radiographs alone. The first model built de novo with only the radiological image as input had an accuracy of 70%. The final model, which was built by fine-tuning a publicly available model named DenseNet, combining the AP and lateral radiographs, and incorporating information from the patient’s history, had an accuracy, sensitivity, and specificity of 88.3%, 70.2%, and 95.6% on the independent test dataset. It performed better for cases of revision THA with an accuracy of 90.1%, than for cases of revision TKA with an accuracy of 85.8%. Conclusion This study showed that machine learning can detect prosthetic loosening from radiographs. Its accuracy is enhanced when using highly trained public algorithms, and when adding clinical data to the algorithm. While this algorithm may not be sufficient in its present state of development as a standalone metric of loosening, it is currently a useful augment for clinical decision making. Cite this article: Bone Joint J 2020;102-B(6 Supple A):101–106.

Is early migration enough to explain late clinical loosening of hip prostheses?

Prosthetic loosening has been debated for decades, both in terms of the timing and nature of the triggering events. Multiple radiostereometric studies of hip prostheses have now shown that early migration poses a risk of future clinical failure, but is this enough to explain late clinical loosening? To answer this question, the progression of loosening from initiation to radiographic detection is described; and the need for explanations other than early prosthetic loosening is analysed, such as stress-shielding, particle disease, and metal sensitivity. Much evidence indicates that prosthetic loosening has already been initiated during or shortly after the surgery, and that the subsequent progression of loosening is affected by biomechanical factors, fluid pressure fluctuations and inflammatory responses to necrotic cells and cell fragments, i.e. the concept of late loosening appears to be a misinterpretation of late-detected loosening. Clinical implications: atraumatic surgery and initial prosthetic stability are crucial in ensuring low risk of prosthetic loosening. Cite this article: EFORT Open Rev 2020;5:113-117. DOI: 10.1302/2058-5241.5.190014

Tussilagone Inhibits Osteoclastogenesis and Periprosthetic Osteolysis by Suppressing the NF-κb and p38 MAPK Signaling Pathways

Backgroud: Aseptic prosthetic loosening is one of main factor producing poor prognosis of limb function after joint replacement and requiring troublesome revision surgery. It is featured by wear particle–induced periprosthetic osteolysis mediated by excessive osteoclasts activated in inflammatory cell context. In our previous study, some natural compounds showing anti-osteoclast trait with high cost-efficiency and few side effects. Tussilagone (TUS), as the main functional extract from Tussilago Farfara precedently used for relieving cough, asthma and eliminating phlegm in traditional medicine, has been proved to appease several RAW264.7-mediated inflammatory diseases via suppressing osteoclast-related signaling cascades. However, whether and how TUS can improve aseptic prosthetic loosening via modulating osteoclast-mediated bone resorption still need to be answered. Methods: We established a murine calvarial osteolysis model to detect the preventative effect of TUS on osteolysis in vivo. Micro-CT scanning and histomorphometric analysis were used to determine the variation of bone resorption and osteoclastogenesis in samples. The anti-osteoclast-differentiation and anti-bone-resorption bioactivities of TUS in vitro were investigated using bone slice resorption pit evaluation and interference caused by cytotoxicity of TUS was excluded according to CCK-8 assay. Quantitative PCR analysis was applied to prove the decreased expression of osteoclast-specific genes after TUS treatment. The inhibition effect of TUS on NF-κb and p38 MAPK signaling pathways was testified by western blotting and NF-κB-linked luciferase reporter gene assay.Results: TUS demonstrated bone protective effect against osteolysis in murine calvarial osteolysis model with reduced osteoclasts compared to the control group. Following studies in vitro witnessed that TUS exert anti-osteoclastogenesis and anti-bone-resorption effects in both BMMs and RAW264.7 cells, as evidenced by the decline of osteoclast specific genes according to quantative PCR. Western blotting revealed that TUS-treated demonstrated inhibited IκBα degradation and p38 phosphorylation.Conclusions: Collectively, for the first time our studies prove that TUS inhibits osteoclastogenesis by suppressing the NF-κb and p38 MAPK signaling pathways, therefore serving as a potential natural compound to treat periprosthetic osteolysis-induced aseptic prosthetic loosening.