Bimekizumab treatment in patients with active axial spondyloarthritis: 52-week efficacy and safety from the randomised parallel phase 3 BE MOBILE 1 and BE MOBILE 2 studies.

OBJECTIVES: Bimekizumab (BKZ), a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A, has demonstrated superior efficacy versus placebo in patients with non-radiographic (nr-) and radiographic (r-) axial spondyloarthritis (axSpA) at Week 16. Here, the objective is to report the efficacy and safety of BKZ at Week 52. METHODS: BE MOBILE 1 (nr-axSpA; NCT03928704) and BE MOBILE 2 (r-axSpA; NCT03928743) comprised a 16-week, double-blind, placebo-controlled period, then a 36-week maintenance period. From Week 16, all patients received subcutaneous BKZ 160 mg every 4 weeks. RESULTS: Improvements versus placebo in Assessment of SpondyloArthritis International Society ≥40% response (primary endpoint), Ankylosing Spondylitis Disease Activity Score, high-sensitivity C-reactive protein levels and MRI inflammation of the sacroiliac joints/spine at Week 16 were sustained to Week 52 in BKZ-randomised patients. At Week 52, responses of patients switching from placebo to BKZ at Week 16 were comparable to BKZ-randomised patients. At Week 52, ≥1 treatment-emergent adverse events (TEAEs) were reported in 183 (75.0%) and 249 (75.5%) patients with nr-axSpA and r-axSpA, respectively. Serious TEAEs occurred in 9 (3.7%) patients with nr-axSpA and 20 (6.1%) patients with r-axSpA. Oral candidiasis was the most frequent fungal infection (nr-axSpA: 18 (7.4%); r-axSpA: 20 (6.1%)). Uveitis occurred in three (1.2%) and seven (2.1%) patients with nr-axSpA and r-axSpA, and inflammatory bowel disease in two (0.8%) and three (0.9%). CONCLUSIONS: At Week 52, dual inhibition of IL-17A and IL-17F with BKZ resulted in sustained efficacy across the axSpA spectrum; the safety profile was consistent with the known safety of BKZ. TRIAL REGISTRATION NUMBER: NCT03928704; NCT03928743.

In Vivo Kinematics and Cruciate Ligament Tension Are Not Restored to Normal After Bicruciate-Preserving Arthroplasty.

BACKGROUND: Whether cruciate ligament forces in cruciate-preserving designs, such as unicompartmental knee arthroplasty (UKA) or bi-cruciate-retaining total knee arthroplasty (BCR-TKA), differ from those in normal knees remains unknown. The purpose of this study was to compare the in vivo kinematics and cruciate ligament force in knees before and after UKA or BCR-TKA to those in normal knees during high-flexion activity. METHODS: Overall, twenty normal knees, 17 knees with medial UKA, and 15 knees with BCR-TKA were fluoroscopically examined while performing a squatting activity. A 2-dimensional or 3-dimensional registration technique was employed to measure tibio-femoral kinematics. Ligament strains and tensions in the anteromedial bundle of the anterior cruciate ligament and posterolateral bundle of the anterior cruciate ligament and the anterolateral bundle of the posterior cruciate ligament (aPCL) and posteromedial bundle of the posterior cruciate ligament (pPCL) during knee flexion were analyzed. RESULTS: Tension in both bundles of the anterior cruciate ligament decreased with flexion. At 60° of flexion, anteromedial bundle of the anterior cruciate ligament tension in postoperative UKA knees was greater than that in normal knees. At 30° of flexion, posterolateral bundle of the anterior cruciate ligament tension in postoperative UKA knees was greater than that in normal knees. On the other hand, aPCL and pPCL tensions increased with flexion. From 40 to 110° of flexion, the postoperative aPCL tension in UKA knees was greater than that in normal knees. At 110° of flexion, the preoperative pPCL tension in UKA knees was greater than that in normal knees. In addition, the postoperative pPCL tension in UKA knees was larger than that in normal knees beyond 20° of flexion. Furthermore, the pPCL tension of postoperative BCR-TKA knees was larger than that in normal knees from 20 to 50° and beyond 90° of flexion. CONCLUSIONS: The cruciate ligament tensions, especially posterior cruciate ligament tension in knees after UKA, were greater than those in the normal knees. Surgeons performing bi-cruciat-preserving knee arthroplasties should therefore balance cruciate ligament tension more carefully in flexion and extension.

Efficacy and safety of bimekizumab in axial spondyloarthritis: results of two parallel phase 3 randomised controlled trials.

OBJECTIVES: Axial spondyloarthritis (axSpA) is a complex disease with diverse manifestations, for which new treatment options are warranted. BE MOBILE 1 (non-radiographic (nr)-axSpA) and BE MOBILE 2 (radiographic axSpA (r-axSpA)) are double-blind, phase 3 trials designed to evaluate efficacy and safety of bimekizumab, a novel dual interleukin (IL)-17A and IL-17F inhibitor, across the axSpA spectrum. METHODS: In parallel 52-week trials, patients with active disease were randomised 1:1 (nr-axSpA) or 2:1 (r-axSpA) to bimekizumab 160 mg every 4 weeks:placebo. From week 16, all patients received bimekizumab 160 mg every 4 weeks. Primary (Assessment of SpondyloArthritis international Society ≥40% improvement (ASAS40)) and secondary endpoints were assessed at week 16. Here, efficacy and treatment-emergent adverse events (TEAEs) are reported up to week 24. RESULTS: 254 patients with nr-axSpA and 332 with r-axSpA were randomised. At week 16, primary (ASAS40, nr-axSpA: 47.7% bimekizumab vs 21.4% placebo; r-axSpA: 44.8% vs 22.5%; p<0.001) and all ranked secondary endpoints were met in both trials. ASAS40 responses were similar across TNFi-naïve and TNFi-inadequate responder patients. Improvements were observed in Ankylosing Spondylitis Disease Activity Score (ASDAS) states and objective measures of inflammation, including high-sensitivity C-reactive protein (hs-CRP) and MRI of the sacroiliac joints and spine. Most frequent TEAEs with bimekizumab (>3%) included nasopharyngitis, upper respiratory tract infection, pharyngitis, diarrhoea, headache and oral candidiasis. More fungal infections (all localised) were observed with bimekizumab vs placebo; no major adverse cardiovascular events (MACE) or active tuberculosis were reported. Incidence of uveitis and adjudicated inflammatory bowel disease was low. CONCLUSIONS: Dual inhibition of IL-17A and IL-17F with bimekizumab resulted in significant and rapid improvements in efficacy outcomes vs placebo and was well tolerated in patients with nr-axSpA and r-axSpA.

Basic fibroblast growth factor promotes meniscus regeneration through the cultivation of synovial mesenchymal stem cells via the CXCL6-CXCR2 pathway.

OBJECTIVE: To investigate the efficacy of basic fibroblast growth factor (bFGF) in promoting meniscus regeneration by cultivating synovial mesenchymal stem cells (SMSCs) and to validate the underlying mechanisms. METHODS: Human SMSCs were collected from patients with osteoarthritis. Eight-week-old nude rats underwent hemi-meniscectomy, and SMSCs in pellet form, either with or without bFGF (1.0 × 106 cells per pellet), were implanted at the site of meniscus defects. Rats were divided into the control (no transplantation), FGF (-) (pellet without bFGF), and FGF (+) (pellet with bFGF) groups. Different examinations, including assessment of the regenerated meniscus area, histological scoring of the regenerated meniscus and cartilage, meniscus indentation test, and immunohistochemistry analysis, were performed at 4 and 8 weeks after surgery. RESULTS: Transplanted SMSCs adhered to the regenerative meniscus. Compared with the control group, the FGF (+) group had larger regenerated meniscus areas, superior histological scores of the meniscus and cartilage, and better meniscus mechanical properties. RNA sequencing of SMSCs revealed that the gene expression of chemokines that bind to CXCR2 was upregulated by bFGF. Furthermore, conditioned medium derived from SMSCs cultivated with bFGF exhibited enhanced cell migration, proliferation, and chondrogenic differentiation, which were specifically inhibited by CXCR2 or CXCL6 inhibitors. CONCLUSION: SMSCs cultured with bFGF promoted the expression of CXCL6. This mechanism may enhance cell migration, proliferation, and chondrogenic differentiation, thereby resulting in superior meniscus regeneration and cartilage preservation.

Bicruciate-retaining total knee arthroplasty procedure reduced tensile force in the middle and posterior components of lateral collateral ligament during deep knee flexion activities with no effect on tensile force of the medial collateral ligament.

PURPOSE: To analyse the effects of bicruciate-retaining total knee arthroplasty (BCR-TKA) on the tensile force of the collateral ligaments during two deep knee flexion activities, cross-leg sitting and squatting. METHODS: Thirteen patients (15 knees) treated using bicruciate-retaining total knee arthroplasty (BCR-TKA) for knee joint osteoarthritis were analysed. Knee joint kinematics during cross-leg sitting (open-chain flexion) and squatting (closed-chain flexion) were evaluated through fluoroscopy. The tensile force was calculated in vivo based on the change in the distance between the femoral and tibial attachment areas for the anterior, middle, and posterior components of the superficial (sMCL) and deep (dMCL) medial collateral ligament and the lateral collateral ligament (LCL). Differences in the calculated tensile forces of the collateral ligaments were evaluated using repeated measures of analysis of variance, with post hoc pairwise comparison (Bonferroni test). Statistical significance was set at P ≤ 0.05. RESULTS: The correction of the coronal alignment was related to the surgical technique, not to the implant design. No significant change in the tensile force in all three components of the sMCL from pre- to post-TKA (n.s.) was observed. For dMCL, a pre- to post-TKA change in the tensile force was observed only for the anterior dMCL component (p = 0.03). No change was observed in the tensile force of the anterior LCL with increasing flexion, with no difference in pre- to post-TKA and between activities (n.s.). In contrast, tensile force in the middle LCL slightly decreased with increasing flexion during squatting, pre- and post-TKA. After surgery, lower forces were generated at 40° of flexion (p = 0.04). Tensile force in the posterior LCL was higher in extension than flexion, which remained high in the extension post-TKA. However, after surgery, lower tensile forces were generated at 10° (p = 0.04) and 40° (p = 0.04) of flexion. CONCLUSIONS: The in vivo change in tensile forces of the collateral ligaments of the knee before and after BCR-TKA can inform the development of appropriate ligament balancing strategies to facilitate recovery of deep knee flexion activities after TKA, as well as for continued improvement of BCR-TKA designs. LEVEL OF EVIDENCE: III.

Feasibility and applicability of locomotive syndrome risk test in elderly patients who underwent total knee arthroplasty.

OBJECTIVES: The concept of locomotive syndrome (LS) and its evaluation method, the LS risk test, have been applied in an integrated manner to capture the decline in mobility resulting from musculoskeletal disorders. The purpose of this study was to evaluate the impact of total knee arthroplasty (TKA) in the elderly with knee osteoarthritis, a common disorder found in LS. METHODS: A total of 111 patients were registered prior to TKA and postoperatively followed up for 1 year. Three components of the LS risk test (the two-step test, stand-up test, and Geriatric Locomotive Function Scale-25) were assessed pre- and postoperatively. RESULTS: After surgery, all three components of the test showed significant improvements from the baseline. The ratio of Stage 3 LS patients (progressed stage of decrease in mobility) reduced from 82.3% to 33.9% postoperatively. There was no significant difference in the degree of change in the scores between the younger (60-74 years) and older (≥75 years) age groups. CONCLUSIONS: We found that TKA has a major impact in preventing the progression of LS in patients with knee osteoarthritis. The LS risk test is a feasible tool for the longitudinal evaluation of patients with musculoskeletal diseases of varying severity and with multiple symptoms.

Pro and contra: is synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) a spondyloarthritis variant?

PURPOSE OF REVIEW: The purpose of this review is to present the up-to-date evidence on the epidemiology, pathogenesis, musculoskeletal manifestations, and imaging of the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome and to discuss its relationship with spondyloarthritis (SpA). RECENT FINDINGS: SAPHO is a rare inflammatory disorder of bone, joints, and skin, with a worldwide distribution that predominantly affects the middle-age adults. The hallmark of the syndrome is a constellation of sterile inflammatory osteitis, hyperostosis, and synovitis involving the anterior chest wall, associated with acneiform and neutrophilic dermatoses, such as palmoplantar pustulosis and severe acne. The axial skeleton, sacroiliac, and peripheral joints can be involved in a similar fashion to SpA. The pathogenesis of the syndrome is multifactorial. The diagnosis is mainly based on the clinical and typical radiological features. The treatment approach is based on the off-label use of antibiotics, bisphosphonates, disease-modifying antirheumatic drugs, and anticytokine biologics. SUMMARY: The SAPHO syndrome shares common features with SpA-related diseases, yet also shows some unique pathogenetic and clinical features. The nosology of SAPHO remains a subject of controversy, awaiting further research into the pathogenetic and clinical aspects of this syndrome. A better understanding of these aspects will improve the diagnostics and clinical care of patients with SAPHO.

Enhanced expression of mRNA for transforming growth factor ß activated kinase 1 in CD34+ cells of the bone marrow in rheumatoid arthritis.

OBJECTIVES: Transforming growth factor ß activated kinase 1 (TAK1) has been found to mediate maladaptive tumour necrosis factor (TNF) signalling, leading to hyperactive downstream nuclear factor Kappa ß (NF-κB) signalling. We explored the expression of TAK1 mRNA in bone marrow CD34+ cells in rheumatoid arthritis (RA) to delineate the mechanism for their abnormal response to TNF-α and differentiate into fibroblast-like cells. METHODS: CD34+ cells were purified from bone marrow samples obtained from 47 RA patients and 27 osteoarthritis (OA) patients during joint operations via aspiration from the iliac crest. The expression of mRNAs for TAK1 and NFκB1 was examined by quantitative RT-PCR. RESULTS: TAK1 mRNA expression in bone marrow CD34+ cells was significantly higher in RA than in OA (TAK1/ß-actin: [11.980 ± 2.380] x 10-3 and [5.593±1.307] x 10-3 [mean ± SEM], respectively; p=0.0238). TAk1 mRNA expression was not different depending on the type of operated joints or on the severity type of RA. Nor was it correlated with serum CRP or rheumatoid factor or with administration of methotrexate, other conventional synthetic disease-modifying anti-rheumatic drugs or oral glucocorticoid. TAK1 mRNA expression was significantly correlated with NFκB1 mRNA expression in RA bone marrow CD34+ cells. CONCLUSIONS: These results indicate that TAK1 mRNA expression is enhanced in bone marrow CD34+ cells independently of the clinimetrics or treatment in RA. It is also suggested that the upregulation of TAK1 mRNA expression might lead to the enhanced expression of NFκB1 mRNA in bone marrow CD34+ cells, but possibly not vice versa, resulting in their abnormal response to TNF-α.

Axial Spondyloarthritis in Japan.

PURPOSE OF REVIEW: The differences in the epidemiology and management of patients with axial spondyloarthritis (axSpA) among regions and countries largely depend on the positivity of human leukocyte antigen (HLA)-B27 and the health care system. This review article focused on axSpA in Japan, where the prevalence of HLA-B27 is extremely low (0.3%) and the universal health insurance system typically provides a 70% or more copayment by the government. RECENT FINDINGS: A nationwide survey was conducted in Japan in 2018, which estimated that there were 3200 patients (95% confidence interval [CI]: 2400-3900) with ankylosing spondylitis (AS), a term interchangeable with radiographic axSpA (r-axSpA), and 800 patients (95% CI: 530-1100) had non-radiographic (nr)-axSpA. These data indicate a prevalence of 2.6/100,000 or 0.0026% for AS and 0.6/100,000 or 0.0006% for nr-axSpA. Patients with AS, but not those with nr-axSpA, are designated as suffering from intractable diseases in Japan; thus, their medical expenses are reduced by grant under the Act on Medical Care for Patients with Intractable Diseases. As of February 2022, infliximab, adalimumab, secukinumab, ixekizumab, and brodalumab have been approved for AS, and secukinumab, ixekizumab, and brodalumab have been approved for nr-axSpA. An algorithm for nr-axSpA in Japan has been developed for the proper diagnosis and use of these therapeutic agents. A low prevalence of axSpA, especially that of nr-axSpA, was found in Japan. Early referral and the resultant diagnosis and appropriate treatment of these patients by rheumatologists are crucial issues in Japan, as in other countries.

Clinical characteristics of patients with spondyloarthritis and inflammatory bowel disease versus inflammatory bowel disease-related arthritis.

The purpose of this study was to clarify the clinical characteristics of spondyloarthritis (SpA) patients with inflammatory bowel disease (IBD) compared to those without IBD. Furthermore, among patients with SpA and IBD, we aimed to clarify what clinical characteristics lead rheumatologists to diagnose "IBD-related arthritis." Utilizing SpA and psoriatic arthritis (PsA) patients' data from an international, cross-sectional, observational study, we analyzed information on demographics and disease characteristics, dichotomizing patients by IBD status. The presence or absence of IBD was determined based on data collection of treating rheumatologists. Patients with SpA (including PsA) and IBD were also categorized based on treating rheumatologists' definitive diagnosis in regard to SpA type, and compared by whether the patients had IBD-related arthritis or not. Among 4465 SpA patients, 287 (6.4%, 95%CI 5.7-7.2%) were identified with IBD. Compared to SpA patients without IBD, patients with SpA and IBD had a longer diagnostic delay (5.1 vs. 2.9 years, p < 0.001). In patients with SpA and IBD, 111 (38.7%, 95%CI 33.0-44.6%) were diagnosed with IBD-related arthritis. Multivariable analyses showed that HLA-B27 positivity [OR = 0.35, (95%CI 0.15-0.80)], psoriasis [OR = 0.14, (95%CI 0.04-0.50)], IBD as first symptom of SpA [OR = 3.32, (95%CI 1.84-6.01)], and need for IBD-specific treatment [OR = 5.41, (95%CI 2.02-14.50)] were independently associated with the definitive diagnosis of IBD-related arthritis. Collaboration with gastroenterologists is needed to shorten the diagnostic delay in patients with SpA and IBD. The recognition of the factors for the diagnosis of "IBD-related arthritis" may lead to the elucidation of the pathogenesis.

In Vivo three-dimensional kinematics of normal knees during sitting sideways on the floor.

BACKGROUND: The normal knee kinematics during asymmetrical kneeling such as the sitting sideways remains unknown. This study aimed to clarify in vivo kinematics during sitting sideways of normal knees. METHODS: Twelve knees from six volunteers were examined. Under fluoroscopy, each volunteer performed a sitting sideways. A two-dimensional/three-dimensional registration technique was used. The rotation angle, varus-valgus angle, anteroposterior translation of the medial and lateral sides of the femur relative to the tibia, and kinematic pathway in each flexion angle was evaluated. RESULTS: Bilateral knees during sitting sideways showed a femoral external rotation relative to the tibia with flexion (ipsilateral: 13.7 ± 3.5°, contralateral: 5.8 ± 6.8°). Whereas the ipsilateral knees showed valgus movement of 4.6 ± 2.5° from 130° to 150° of flexion, and the contralateral knees showed varus movement of -3.1 ± 4.4° from 110° to 150° of flexion. The medial side of the contralateral knees was more posteriorly located than that of the ipsilateral knees beyond 110° of flexion. The lateral side of the contralateral knees was more anteriorly located than that of the ipsilateral knees from 120° to 150° of flexion. In the ipsilateral knees, a medial pivot pattern followed by a bicondylar rollback was observed. In the contralateral knees, no significant movement followed by a bicondylar rollback was observed. CONCLUSION: Even though the asymmetrical kneeling such as sitting sideways, the knees did not display asymmetrical movement.

Femoral rollback at high-flexion during squatting is related to the improvement of sports activities after bicruciate-stabilized total knee arthroplasty: an observational study.

BACKGROUND: In bicruciate-stabilized total knee arthroplasty (BCS-TKA), the relationship between the postoperative kinematics and sports subscales in patient-reported outcome measures (PROMs) remains unknown. The purpose of this study was to determine the relationship between kinematics and sports subscales using the PROMs after BCS-TKA. METHODS: Sixty-one patients with severe knee osteoarthritis were examined at 13.5 ± 7.8 months after BCS-TKA. The patients performed squats under single fluoroscopic surveillance in the sagittal plane. Range of motion of the knee, axial rotation of the femur relative to the tibial component, and anteroposterior (AP) translation of the medial and lateral femorotibial contact points were measured using a 2D-to-3D registration technique. In addition, the relationship between the kinematics and improvement of the sports subscales in the Knee Injury and Osteoarthritis Outcome Score (KOOS) was evaluated. RESULTS: In rotation angle, the femoral external rotation was observed from 0 to 50° of flexion. The amount of femoral external rotation did not correlate with PROMs-SP. In medial AP translation, posterior translation was observed from 0 to 20° and 80-110° of flexion. Mild anterior translation was observed from 20 to 80° of flexion. Beyond 80° of flexion, posterior translation was positively correlated with squatting. In lateral AP translation, posterior translation was observed from 0 to 20° and 80-110° of flexion. Beyond 80° of flexion, posterior translation was positively correlated with running, jumping, twisting/pivoting, and kneeling. CONCLUSION: Femoral rollback at high flexion during squatting may be important to improve sports performance after BCS-TKA.

The higher patient-reported outcome measure group had smaller external rotation of the femur in bicruciate-stabilized total knee arthroplasty.

PURPOSE: The hypothesis of this study was that the kinematics of patients with higher patient-reported outcome measures (PROMs) differ from those of patients with lower PROMs after bicruciate-stabilized total knee arthroplasty (BCS-TKA). METHODS: A total of 32 patients with severe knee osteoarthritis were examined 11.2 ± 3.2 months after BCS-TKA. The patients performed squats under single fluoroscopic surveillance in the sagittal plane. To estimate the spatial position and orientation of the femoral and tibial components, a 2D-to-3D registration technique was used. This technique uses a contour-based registration algorithm, single-view fluoroscopic images and 3D computer-aided design models. Knee range of motion, varus-valgus alignment, axial rotation of the femur relative to the tibial component, anteroposterior translation of the medial and lateral femorotibial contact points, kinematic paths, and anterior and posterior post-cam engagement were measured. The patients were divided into two groups using hierarchical cluster analysis based on the 1-year postoperative Knee Injury and Osteoarthritis Outcome Score and 2011 Knee Society Score. RESULTS: The femoral component had significantly more external rotation in the low-score group than in the high-score group (5.1 ± 1.8° vs. 2.2 ± 2.7°, p = 0.02). The high-score group had a medial pivot pattern from 0 to 20° of flexion, without significant movement from 20 to 70°, and final bicondylar rollback beyond 70°. The low-score group had a medial pivot from 0 to 70° of flexion and bicondylar rollback beyond 70°. There were no significant between-group differences in the varus-valgus angle or post-cam engagement. CONCLUSION: The higher PROM group had smaller external rotation of the femur after BCS-TKA. LEVEL OF EVIDENCE: Level III.

SAPHO syndrome and pustulotic arthro-osteitis.

Synovitis-Acne-Pustulosis-Hyperostosis-Osteitis (SAPHO) syndrome is a rare inflammatory osteoarticular disorder, which encompassed many diseases, including pustulotic arthro-osteitis (PAO). Musculoskeletal manifestations, including osteitis, synovitis, and hyperostosis, are the hallmarks of the SAPHO syndrome and affect a variety of regions of the body. Recent survey indicated that more than 80% of cases of SAPHO syndrome in Japan were PAO, originally proposed by Sonozaki et al. in 1981, whereas severe acne was the most commonly reported skin ailment amongst participants with SAPHO syndrome in Israel. Prevalence of SAPHO syndrome remains unavailable, whereas the prevalence of palmoplantar pustulosis (PPP) was reported to be 0.12% in Japan, and 10-30% of patients with PPP had PAO. SAPHO syndrome and PAO are predominantly found in patients in the third through fifth decades of life, and a female predominance is seen in both groups. The diagnosis is typically made by a rheumatologist or dermatologist. Identification of a variety of the clinical, radiological, and laboratory features outlined, as well as diagnostic criteria, are used to make the diagnosis. Goals of treatment seek to maximize health-related quality of life, preventing structural changes and destruction, and normalizing physical function and social participation. Finally, we review the non-pharmacological and pharmacological managements.

A nationwide questionnaire survey on the prevalence of ankylosing spondylitis and non-radiographic axial spondyloarthritis in Japan.

OBJECTIVE: This nationwide study aimed to reveal the prevalence of ankylosing spondylitis (AS), non-radiographic axial spondyloarthritis (nr-ax SpA), and the positivity rate of human leukocyte antigen (HLA) among such patients in Japan. METHODS: The first survey was conducted in 2221 randomly selected facilities (26.3%) in September 2018, where the patients with AS/nr-ax SpA were taken care of from January to December 2017. We estimated the total number of these patients using response and extraction rates. A second survey was conducted in 117 facilities (49.8%) to assess for HLA-B27 positivity rate and clinical features. RESULTS: The estimated total numbers of the patients with AS and nr-ax SpA were 3200 (95% confidence interval [CI]: 2400-3900) and 800 (530-1100), suggesting that the prevalence values of AS and nr-ax SpA in general population were 2.6/100,000 (0.0026%) and 0.6/100,000 (0.0006%), respectively. Although 55.5% (76/137) of patients with AS were HLA-B27-positive, those whose age of onset was estimated to be over 50 years tended to undergo less HLA-B27 testing. CONCLUSION: This study revealed the lower prevalence of AS/nr-ax SpA in Japan, compared to those in other countries. Further studies are required to reveal the association of HLA-B27 with the clinical features.

Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial.

BACKGROUND: Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. METHODS: COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352. FINDINGS: Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. INTERPRETATION: Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. FUNDING: Eli Lilly and Company.

Weight-bearing knee flexion angle better correlates with patient-reported outcome measures than non-weight-bearing condition in total knee arthroplasty: a three-dimensional analysis study.

BACKGROUND: This study aims to elucidate and compare the relationship between the knee flexion angle and patient-reported outcome measures (PROM) in both non-weight-bearing (NWB) and weight-bearing (WB) conditions. METHODS: This retrospective cohort study included 61 knees (47 patients) who underwent total knee arthroplasty. The knee flexion angle was measured by three conditions: NWB in manual goniometer, NWB in fluoroscopic three-dimensional (3D) analysis and WB in the fluoroscopic 3D analysis. The PROM was evaluated by postoperative 2011 Knee Society Score (2011 KSS) and Knee injury and Osteoarthritis Outcome Score (KOOS). Correlations between the knee flexion angle and PROM was analyzed using Spearman's correlation coefficient. Additionally, whether the angular difference between NWB and WB correlated with the PROM or not was evaluated. RESULTS: The NWB knee flexion angle in a goniometer, NWB in 3D analysis, and WB in 3D analysis were 124.6° ± 8.4°, 118.0° ± 10.5°, and 109.5° ± 13.3°, respectively. The angular difference was 8.5° ± 12.8°. No PROM correlation existed in NWB using a goniometer. Moreover, significant positive correlations in 2011 KSS symptoms (r = 0.35) and 2011 KSS functional activities (r = 0.27) were noted in NWB using 3D analysis. Significant positive correlations existed in 2011 KSS symptoms (r = 0.32), 2011 KSS functional activities (r = 0.57), KOOS pain (r = 0.37), KOOS activity of daily living (ADL; r = 0.45), KOOS sports (r = 0.42), and KOOS quality of life (r = 0.36) in WB using 3D analysis. Significant negative correlations were noted in 2011 KSS functional activities (r = - 0.45), KOOS ADL (r = - 0.30), and KOOS sports (r = - 0.38) in angular difference. CONCLUSIONS: The WB knee flexion angle better correlated with PROM compared with NWB by evaluation of 3D analysis. The larger the angular difference existed between NWB and WB, the lower the PROM score.

Weight-bearing status affects in vivo kinematics following mobile-bearing unicompartmental knee arthroplasty.

PURPOSE: The effects of weight bearing (WB) on knee kinematics following mobile-bearing unicompartmental knee arthroplasty (UKA) remain unknown. The purpose of this study was to clarify the effects of WB on in vivo kinematics of mobile-bearing UKA during high knee flexion activities. METHODS: The kinematics of UKA were evaluated under fluoroscopy during squatting (WB) and active-assisted knee flexion (non-weight bearing, NWB). Range of motion, femoral axis rotation relative to the tibia, anteroposterior (AP) translation of the medial and lateral sides, and kinematic pathway were measured. RESULTS: There were no differences in knee flexion range and external rotation of the femur in each flexion angle between the WB conditions. The amount of femoral external rotation between minimum flexion and 60° of flexion during WB was significantly larger than that during NWB, and that between 60° and 130° of flexion during NWB was significantly larger than that during WB. There were no differences in medial AP translation of the femur in each flexion angle between the WB conditions. However, on the lateral side, posterior translation of 52.9 ± 12.7% was observed between minimum flexion and 130° of flexion during WB. During NWB, there was no significant translation between minimum flexion and 60° of flexion; beyond 60° of flexion, posterior translation was 41.6 ± 8.7%. Between 20° and 80° of flexion, the lateral side in WB was located more posteriorly than in NWB (p < 0.05). CONCLUSION: Mobile-bearing UKA has good anterior stability throughout the range of knee flexion. WB status affects the in vivo kinematics following mobile-bearing UKA. LEVEL OF EVIDENCE: III.

Treatment patterns and health care resource utilization among Japanese patients with ankylosing spondylitis: A hospital claims database analysis.

OBJECTIVES: To understand the current state of treatment patterns and health care resource utilization among patients in Japan with ankylosing spondylitis (AS) managed in the real-world setting. METHODS: Patient records from the Medical Data Vision database were analyzed to identify patients with ICD-10 AS from April 2009 through July 2017. Measures evaluated included demographic, clinical, and other characteristics at diagnosis; treatment patterns; health care resource utilization; and costs. RESULTS: Four hundred and seventeen patients met the study's inclusion criteria. Treatments observed during the first year after the initial AS diagnosis included nonsteroidal anti-inflammatory drugs (79.6%), corticosteroids (39.3%), methotrexate (22.3%), sulfasalazine (16.8%), adalimumab (14.2%), and infliximab (12.2%). At any time during the mean 33 months of study follow-up, biologic disease-modifying antirheumatic drugs (bDMARDs) were initiated by 115 patients. During the study follow-up, patients who initiated bDMARDs had higher median total per-patient annual health care costs ($26,937 vs $15,323), lower median per-patient hospitalization costs ($29,817 vs. $39,509), and fewer median hospital days per admission (7.0 vs. 11.0 days) compared with the overall group of patients diagnosed with AS. CONCLUSION: This database study provides knowledge of patient characteristics, treatment patterns, HCRU, and costs for patients with AS in Japan. The study outcomes demonstrate a need for increased awareness of proper AS management.

Non-radiographic axial spondyloarthritis.

Non-radiographic axial spondyloarthritis (nr-axSpA) is a subgroup of axial spondyloarthritis (axSpA) without fulfilling the modified New York criteria of sacroiliac joint radiographs for ankylosing spondylitis (AS). AS and nr-axSpA share various demographic and clinical features and disease burden, although sex and objective inflammatory findings such as elevated serum C-reactive protein level are slightly different between AS and nr-axSpA. Recently, diagnostic guidance for nr-axSpA in Japan was proposed for epidemiological studies of a population with a low prevalence of HLA-B27 positivity and the use of molecular targeted agents suitable for the unique medical care system in Japan. A biological agent targeting interleukin-17 was approved for nr-axSpA by the Pharmaceutical and Medical Devices Agency (PMDA) in August 2020. Some other biological agents will be also available for Japanese patients with nr-axSpA in the near future.