Prevalence and radiographic features of atlantoaxial dislocation in adult patients with Kashin-Beck disease.

PURPOSE: Kashin-Beck disease (KBD) is an endemic osteoarthropathy affecting the epiphyseal growth plate of multiple joints in young and adolescent patients. Previous studies have focused on the visible deformed extremities instead of the spinal radiological features, especially the atlantoaxial joint. The aim of this study was to determine the prevalence and radiographic features of atlantoaxial dislocation (AAD) in adult patients with KBD. METHODS: This study was conducted on KBD patients in three typical endemic counties between October 2017 and November 2019. The patients were evaluated by collecting basic information, clinical signs and symptoms. They underwent dynamic cervical radiography, by which AAD was diagnosed. For those patients with confirmed or suspected AAD, computed tomography (CT) imaging was performed to observe the odontoid morphology and degenerative changes in the lateral atlantoaxial joints. Radiographic evaluations were reviewed to determine the prevalence and features of AAD. RESULTS: A total of 39 (14.6%) of 267 KBD patients were diagnosed with AAD. Compared with the non-AAD patients, the detection rate of AAD was associated with a longer disease duration and stage and was not associated with age, sex or BMI. Thirty-two patients had symptoms at the neck or neurological manifestations, while seven had no symptoms. There were three types of morphologies of the odontoid process in AAD patients: separating in 19 cases, hypoplastic in 15 cases and intact in five cases. Anterior dislocation was noted in 29 cases, and posterior dislocation was noted in ten cases. Thirty-four cases were reducible, and five were irreducible. The lateral atlantoaxial joints had different severities of degenerative changes in 17 cases. CONCLUSIONS: This study revealed that the prevalence of AAD was 14.6% in adult KBD patients. The radiographic features of AAD include manifestations of odontoid dysplasia and chronic degenerative changes in atlantoaxial joints. KBD patients with severe stages and longer disease duration were more vulnerable to the occurrence of AAD. We postulate that this atlantoaxial anomaly might originate from chondronecrosis of the epiphyseal growth plate of the odontoid process in young and adolescent individuals. This study may provide a clinical reference to help clinicians screen, prevent and treat AAD in adult patients with KBD.

DR4-Associated Death Receptor Signal Promotes Cartilage Damage in Patients With Kashin-Beck Disease.

Purpose. To explore the relationship between the death receptor (DR) and the pathological progression of Kashin-Beck disease (KBD). Design. KBD cartilage samples were collected from 15 patients diagnosed according to the "National Diagnostic Criteria of KBD" in China. In vitro monolayer chondrocytes were cultured in complete medium. Caspase-3 and caspase-8 activities in chondrocytes were analyzed using a kit. Nuclear morphology was observed by Hoechst 33258 staining, apoptosis was verified by flow cytometry analysis, and DR molecules were detected using Western blotting and quantitative real-time reverse transcription polymerase chain reaction analysis. Results. Early apoptotic rates of KBD and osteoarthritis (OA) chondrocytes were higher than those of normal control (NC) cells. Excessive apoptotic nuclei were observed in OA and KBD cells after Hoechst 33258 staining. Activities of both caspase-3 and caspase-8 were higher in KBD and OA cells than in NC cells. The average DR4 mRNA level in KBD cells was 3.301-fold higher than that in NC cells, Fas-associating protein with death domain (FADD) transcript level in KBD cells was 2.528-fold higher than that in NC cells. Western blot analyses showed that FAS, DR4, DR5, caspase-3, and FADD were upregulated in the KBD and OA groups compared with the NC group. High expression of caspase-8 in KBD compared with NC was verified, whereas cellular FLICE-inhibitory protein (c-FLIP) in KBD was significantly downregulated. Conclusions. KBD and OA chondrocytes showed obvious FADD-caspase-dependent apoptosis, which is related to the DR pathway. Apoptosis in KBD articular cartilage is mainly related to FAS/DR4-FADD-caspase signaling, and OA is associated with FAS/DR4/DR5-FADD-caspase signaling.

Comparison of the responsiveness of the WOMAC and the 12-item WHODAS 2.0 in patients with Kashin-Beck disease.

BACKGROUND: Several questionnaires have been used to assess the health status of patients with Kashin-Beck disease (KBD) in clinical trials, but the evidence regarding the responsiveness of these instruments in KBD patients is limited. Therefore, the aim of this study was to evaluate and compare the responsiveness of the Chinese version of the Western Ontario and McMaster Universities Osteoarthritis index (WOMAC) and 12-item World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) in KBD patients undergoing intra-articular injection of hyaluronic acid (HA). METHODS: A sample of 232 KBD patients treated with intra-articular injection of HA completed the WOMAC, 12-item WHODAS 2.0 and joint dysfunction index (JDI) both pre- and post-treatment. Responsiveness was assessed using correlation and receiver operating characteristic (ROC) curve analyses following the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. RESULTS: Overall, there were significant improvements in the mean scores on the WOMAC and on the 12-item WHODAS 2.0, except for in the cognition domain. Correlation analysis showed that changes in the WOMAC and 12-item WHODAS 2.0 scores had moderate or weak positive associations with the changes in the JDI. However, acceptable areas under the ROC curve (value > 0.7) were found for all domains and for the total score on the WOMAC, but only for the mobility domain and the total score on the 12-item WHODAS 2.0. CONCLUSIONS: These results demonstrated that the WOMAC was more responsive than the 12-item WHODAS 2.0 in KBD patients treated with intra-articular injection of HA. Our findings support the continued use of the WOMAC as an outcome measure in assessing disability in KBD patients.

Outcomes of total knee arthroplasty in the adult Kashin-Beck disease with severe osteoarthritis.

PURPOSE: Kashin-Beck disease (KBD) is an endemic osteoarthropathy, and the severe knee pain and functional limitations were seriously affecting the quality of life in patients with end-stage KBD. We retrospectively evaluated the clinical outcomes and the quality of life in KBD patients with total knee arthroplasty (TKA). METHODS: A total of 22 subjects (25 knees) suffered KBD with severe knee pain and underwent primary TKA. Knee pain was measured by visual analogue scale (VAS), and the knee function was evaluated by Knee Society Clinical Rating System Score (KSS). KBD Quality of Life (KBDQOL) was used to evaluate the quality of life in KBD patients before and after TKA. RESULTS: There were no major complications after TKA. The levels of VAS score were obviously deceased in post-operation than that in pre-operation. The levels of KSS score were increased in one year after TKA compared with the pre-operative values, and it maintained a higher level on three years after TKA. The average KBDQOL score level of each domain in pre-operation and one and three years after TKA was increased accordingly. The average scores of physical function, activity limitation, support of society, mental health, and general health in one year after TKA were significantly higher than those in pre-operation. CONCLUSIONS: TKA can reduce knee pain, improve knee function, and improve the quality life in KBD patients. KBDQOL questionnaire may be a promising instrument for assessing the quality life in KBD patients.

Accidental or linked: separated odontoid process fused to the enlarged anterior arch of the atlas associated with atlantoaxial subluxation in a Kashin-Beck disease patient.

PURPOSE: KBD is an endemic disease affecting the epiphyseal growth plate and articular cartilage of multiple joints, resulting in extremities' deformation and skeletal dysplasia. More attention has been paid to the visible deformed extremities instead of inconspicuous spinal condition. There is a lack of reports concerning the spinal radiological features, especially for the atlantoaxial joint. The aim of this paper is to report a case of a Kashin-Beck disease (KBD) patient diagnosed with atlantoaxial subluxation, concomitant with separated odontoid process fused to the enlarged anterior arch of the atlas. METHODS: We report the case of a 60-year-old woman with 54 years' history of KBD complaining of occipitocervical pain, decreasing motor strength and sensory function of both upper and lower extremities. Subsequent radiological examinations of lateral plain radiography, computed tomography scans and magnetic resonance imaging were performed to reveal these rare characteristics of atlantoaxial joint in this patient. Then, we review the associated articles to postulate whether this anomaly is accidental or linked in a KBD patient. RESULTS: She had an extremely rare variant with three aspects of characteristics: atlantoaxial subluxation concurrent with severe spinal canal stenosis and spinal cord compression, odontoid process separating from the body of axis, and the enlarged anterior arch of the atlas fusion with odontoid process. Comparing with the congenital anomaly of atlantoaxial joint, we postulated that this aetiology of anomaly might be linked to the acquired form attributed to the histopathology of KBD, rather than an accidental event. CONCLUSIONS: The anomaly of atlantoaxial joint might occur in KBD patients. Larger numbers of KBD candidates with earlier symptoms are recommended for radiological examinations of atlantoaxial joint, especially for the adolescents. Spinal surgeons are suggested to involve the research of the spinal anatomy and variation for the prevention and earlier therapy for KBD patients.

Total hip replacement in adult patients with severe Kashin-Beck disease of the hip.

BACKGROUND: The treatment of elderly patients with Kashin-Beck disease (KBD) remains clinically challenging, and clinical data are very lacking. The aim of this study was to retrospectively evaluate pain and functional outcomes following total hip replacement in adult patients with severe KBD of the hip. METHODS: Twenty-two patients (32 hips) with KBD underwent primary hip replacement and were followed for at least 2 years. Radiographic and Clinical assessments were evaluated for each patient at 2 and 4 weeks and at 3, 6 and 12 months after the operation and annually thereafter. The efficacy index included the visual analogue scale (VAS) score, Harris hip score, functional score for adult Tibetans with Kashin-Beck Disease (FSAT-KBD) and radiographic outcomes. RESULTS: The patients underwent a follow-up, and the mean follow-up time was 3.8 years. VAS scores significantly decreased within the first 6 months postoperatively. This decrease continued until the final follow-up (p < 0.01). This result was supported by a significant increase in the Harris and FSAT-KBD scores after the surgery (p < 0.01). At the final follow-up, there was no change in prosthesis positioning or radiographic evidence of prosthesis loosening. One case received impacted allograft bone croutons and had worn polyethylene components replaced after 6 years because the patient suffered severe pelvic and femoral osteolytic lesions postoperatively. CONCLUSIONS: Hip replacement can relieve pain and improve joint function in treating severe KBD hip. Additional studies that are more extensive are needed to confirm the findings of our study.

Integrative analysis of genome-wide association studies and gene expression profiles identified candidate genes for osteoporosis in Kashin-Beck disease patients.

SUMMARY: The molecular mechanism of osteoporosis (OP) in Kashin-Beck disease (KBD) patients was unclear. Our results suggest that KBD and OP shared some common causal genes, functionally involved in skeletal growth and development and chronic inflammation. Our results provide novel clues for clarifying the molecular mechanism of OP in KBD patients. INTRODUCTION: KBD is a chronic skeletal disorder with osteopenia and OP. The pathogenesis of OP in KBD patients remains elusive. METHODS: A total of 1717 subjects participated in this study. KBD was diagnosed according to the clinical diagnosis criteria of China (GB16395-1996). The bone mineral density (BMD) and bone areas of the ulna and radius, hip, and lumbar (L1-L4) were measured with a Hologic 4500 W dual-energy X-ray absorptiometry scanner. Genotyping was conducted using Affymetrix SNP Array 6.0. Gene expression profiling of peripheral blood mononuclear cells of KBD and OP patients were compared using Affymetrix HG-U133 plus 2.0 arrays and Agilent Human 1A arrays, respectively. Genome-wide association studies (GWAS) were conducted by PLINK. SCEA and DAVID were applied for pleiotropy and functional enrichment analysis, respectively. RESULTS: SCEA analysis observed significant pleiotropic effects between KBD and the ulna and radius BMD (P value = 5.99 × 10(-3)). GWAS meta-analysis identified six candidate genes with pleiotropic effects, including PDGFD, SOX5, DPYD, CTR9, SPP1, and COL4A1. GO analysis identified 16 significant GO shared by KBD and the ulna and radius BMD, involved in cell morphogenesis and apoptosis. Pathway enrichment analysis detected two common pathways for KBD and the ulna and radius BMD, including calcium signaling pathway and vascular smooth muscle contraction pathway. Gene expression analysis detected three up-regulated inflammation-related genes for KBD and OP, including IL1B, IL8, and CCL1. CONCLUSION: This study reported several candidate genes involved in the development of OP in KBD patients.

Long-Term Efficacy of Arthroscopic Debridement on Knee Osteoarthritis in Patients with Kashin-Beck Disease.

Kashin-Beck Disease (KBD) is a chronic and degenerative joint disease with decreased health conditions causing major functional limitations and disability. In this study, we investigated the long-term clinical outcomes of arthroscopic debridement for knee osteoarthritis in KBD patients with Kellgren-Lawrence I-III classification. 31 KBD patients underwent arthroscopic debridement and 24 of them were followed up 8 years after the surgery. The Lysholm scores, femorotibial angle (FTA), and joint space angle (JSA) of the knees were assessed and compared preoperatively and postoperatively to evaluate the clinic outcome. Our results showed that the Lysholm scores, but not the FTA or JSA, of these patients were significantly improved 8 years after the therapy, suggesting that arthroscopic surgery has long-term efficacy in KBD patients with Kellgren-Lawrence I-III classification.

Radiographic features of hand osteoarthritis in adult Kashin-Beck Disease (KBD): the Yongshou KBD study.

OBJECTIVE: Kashin-Beck Disease (KBD) is a rare and severe osteoarthropathy endemic to China. We evaluated the frequency and patterns of hand radiographic osteoarthritis (rOA) in adults with and without KBD. METHODS: Han Chinese (N = 438) from Yongshou County of central China underwent right hand radiography for determining case status. Presence of KBD was based on characteristic radiographic deformities of articular ends of bones including articular surface depression, carpal crowding, any subchondral bone deformities in the proximal end of phalanges or first metacarpal bone, or the distal ends of metacarpal bones 2-5, and any bony enlargement with deformity of the distal ends of phalanges. Hand rOA severity was determined by osteophyte (OST), joint space narrowing (JSN), and Kellgren and Lawrence (KL) grades. RESULTS: This study included 127 KBD and 311 non-KBD adults of similar mean age (39 years) and body mass index (BMI) (21 kg/m(2)). Inter- and intra-rater reliability for radiographic determination of case status and rOA features was high (kappa 0.72-0.96). Compared to non-KBD, KBD adults had significantly more severe hand rOA of the thumb, distal interphalangeal (DIP), proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints. Only KBD adults had end-stage carpometacapal (CMC) disease. In KBD, DIPs and PIPs were more affected than MCPs and the frequency of OSTs was significantly higher in PIPs than DIPs. CONCLUSIONS: Compared with age-matched adults from the same area and farming occupation, KBD hand rOA was more widespread and severe, particularly of PIPs and CMCs. The ability to differentiate adult KBD from non-KBD hand rOA will facilitate genetic analyses of the vast majority of affected individuals.

Increased levels of IL-6, IL-1ß, and TNF-α in Kashin-Beck disease and rats induced by T-2 toxin and selenium deficiency.

The objective of this study is to investigate the possible role of inflammatory mediators such as IL-6, IL-1ß, and TNF-α in Kashin-Beck disease (KBD) children and rats fed with T-2 toxin under a selenium-deficient nutrition status in order to determine possible mechanism underlying KBD. Sprague-Dawley rats were administered a selenium-deficient diet for 4 weeks prior to their exposure to T-2 toxin for 4 weeks. The morphology of joint cartilages of KBD children and rats was examined by light microscopy, and the expression of proteoglycans was determined by histochemical staining. The serum levels of IL-6, IL-1ß, and TNF-α were determined by enzyme-linked immunosorbent assay. IL-6, IL-1ß and TNF-α were localized by immunohistochemistry, and their mRNA levels were detected by real-time RT-PCR. The serum levels of IL-6 were significantly elevated in rats fed with selenium-deficient, T-2 toxin, and T-2 toxin plus selenium-deficient diets compared to those in the normal diet, while the serum levels of IL-1ß and TNF-α were significantly increased only in the T-2 toxin plus selenium-deficient diet group. IL-6, IL-1ß and TNF-α protein and mRNA levels in cartilage were significantly higher in rats with diets of T-2 toxin and T-2 toxin plus selenium deficiency than in rats fed normal or selenium-deficient diet. While staining for the cytokines in cartilages of KBD children was significantly higher than that in controls. T-2 toxin under a selenium-deficient nutritional status induces increased levels of IL-6, IL-1ß, and TNF-α in serum and cartilages, which may account for the pathological mechanism underlying the cartilage damage in KBD.

Autoimmune and inflammatory responses in Kashin-Beck disease compared with rheumatoid arthritis and osteoarthritis.

To examine plasma levels of arthritis-related autoantibodies and inflammatory factors in Kashin-Beck disease (KBD) patients compared with rheumatoid arthritis (RA) patients, osteoarthritis (OA) patients, and healthy controls, the plasma levels of autoantibodies to types II, IX, and XI collagen and cyclic citrullinated peptide (CCP) and immunoglobulin (Ig)-G and IgM rheumatoid factors (IgG-RF and IgM-RF) from 45 KBD patients, 39 RA patients, 46 OA patients, and 30 healthy controls were determined by enzyme-linked immunosorbent assay. The plasma concentrations of nitric oxide (NO) and tumor necrosis factor-α (TNF-α) were measured using the Griess method and bioassay, respectively. Statistical analysis was performed using one-way analysis of variance followed by the least significant difference t test for differences among groups. Results indicated that the plasma levels of collagen IX antibodies, IgG-RF, and NO significantly increased in KBD patients compared with patients with RA and OA and the control group. The levels of collagen XI antibodies, CCP antibodies, and IgM-RF but not collagen II antibodies and TNF-α were significantly increased in the plasma of the KBD group compared with that of the control group. We conclude that autoimmunity and inflammation may be involved in the pathogenesis of KBD, in particular in the advanced stage.

Efficacy of celecoxib, meloxicam and paracetamol in elderly Kashin-Beck disease (KBD) patients.

The objective of this study was to compare the efficacy and tolerability of celecoxib, meloxicam and paracetamol in late Kashin-Beck disease. Adults (n = 168) with Kashin-Beck disease were randomised in clusters to receive six week courses of celecoxib 200 mg once daily, meloxicam 7.5 mg once daily or paracetamol 300 mg three times daily. Efficacy assessments included overall joint pain intensity and Western Ontario and McMaster Universities Osteoarthritis Index subscales; tolerability was evaluated by adverse event and physician reporting. Celecoxib and meloxicam were efficacious in relieving pain and improving stiffness, but unable to improve physical function after six weeks. Paracetamol was efficacious in relieving pain, but unable to improve morning stiffness and physical function after six weeks. Celecoxib and meloxicam provide predictable and sustained relief from pain and stiffness. Paracetamol can relieve the pain. None of the treatments improved impaired physical function in Kashin-Beck disease.

Kashin Beck Disease: more than just osteoarthrosis: a cross-sectional study regarding the influence of body function-structures and activities on level of participation.

The purpose of this study was to investigate the influence of body function, activities and pain on the level of activity in adults with Kashin Beck Disease (KBD). Seventy-five KBD patients with a mean age of 54.8 years (SD 11.3) participated. Anthropometrics, range of joint motion (ROM) and muscle strength were measured as well as the time-up-and-go test and functional tests for the lower and upper extremities. Activity was assessed with the participation scale and the WHO DAS II. In the shoulder, elbow, hip and knee joints, a severe decrease in ROM and bilateral pain was noted. A decrease in muscle strength was observed in almost all muscles. The timed-up-and-go test scores decreased. No or mild restriction in activity was found in 35%, and 33% experienced a moderate restriction whereas 32% had severe to extreme restriction. Activities in the lower extremities were mildly to moderately correlated to ROM and muscle strength, whereas in the upper extremities activities were correlated to range of joint motion. Activity was significantly associated with ROM after correction for muscle strength, gender and age. Participation was borderline significantly associated with ROM after correction for muscle strength, gender, age and the activity time-up-and-go. In KBD adults, a severe decrease in activity is primarily caused by decrease in ROM. These findings have strong influence on rehabilitation and surgical intervention.