Collapse-related bone changes at multidetector CT in ARCO 1-2 osteonecrotic femoral heads: correlation with clinical and MRI data.

OBJECTIVE: To assess the frequency of collapse-related bone changes at multi-detector CT (MDCT) in osteonecrotic femoral heads (ONFH) and to compare clinical parameters and MRI findings in Association Research Circulation Osseous (ARCO) 1-2 ONFH with or without collapse-related bone changes (CRBC) at MDCT. MATERIALS AND METHODS: This is a secondary analysis of radiographic, MRI, and MDCT examinations of ONFH of patients eligible for a prospective clinical trial. Radiographs and MRI were analyzed to perform ARCO staging. Frequency of CRBC at MDCT including cortical interruption, trabecular interruption, impaction, and resorption was determined by two readers (R1, R2) blinded to radiographic, MRI, and clinical data. Baseline clinical and imaging data of ARCO 1-2 ONFH were compared between hips with or without CRBC at MDCT. RESULTS: One hundred thirty-two hips of 77 participants were analyzed. There were 78 non-collapsed and 54 collapsed ONFH. For R1 and R2, 31/78 (40%) and 20/78 (26%) ARCO 1-2 ONFH and 54/54 (100%) and 53/54 (98%) ARCO 3-4 ONFH showed at least one CRBC at MDCT. For both readers, there was no significant difference in pain, functional impairment, size of lesion, and the presence of BME on MRI between ARCO 1-2 hips with or without CRBC at MDCT. CONCLUSION: Twenty-six to forty percent of ARCO 1-2 ONFH demonstrate at least one collapse-related bone change at CT. Their clinical and MRI findings do not differ from those without collapse-related bone changes. KEY POINTS: • Ninety-eight to one hundred percent of collapsed and 26-40% of non-collapsed osteonecrotic femoral heads presented at least one collapse-related bone change at CT (cortical or trabecular bone interruption, trabecular bone impaction, or resorption). • There was no significant difference in age, sex, pain, functional impairment, size of lesion, or frequency of marrow edema on MRI between non-collapsed hips with or without collapse-related bone changes at CT. • The significance of collapse-related bone changes at CT should be further assessed.

Does Adjunction of Autologous Osteoblastic Cells Improve the Results of Core Decompression in Early-stage Femoral Head Osteonecrosis? A Double-blind, Randomized Trial.

BACKGROUND: Osteonecrosis of the femoral head (ONFH) is a disabling disease that can ultimately progress to collapse of the femoral head, often resulting in THA. Core decompression of the femoral head combined with cell therapies have shown beneficial effects in previous clinical studies in patients with early-stage (Association Research Circulation Osseous [ARCO] Stage I and II) ONFH. However, high-quality evidence confirming the efficacy of this treatment modality is still lacking. QUESTIONS/PURPOSES: (1) Is core decompression combined with autologous osteoblastic cell transplantation superior to core decompression with placebo implantation in relieving disease-associated pain and preventing radiologic ONFH progression in patients with nontraumatic early-stage ONFH? (2) What adverse events occurred in the treatment and control groups? METHODS: This study was a Phase III, multicenter, randomized, double-blind, controlled study conducted from 2011 to 2019 (ClinicalTrails.gov registry number: NCT01529008). Adult patients with ARCO Stage I and II ONFH were randomized (1:1) to receive either core decompression with osteoblastic cell transplantation (5 mL with 20 x 10 6 cells/mL in the study group) or core decompression with placebo (5 mL of solution without cells in the control group) implantation. Thirty percent (68 of 230) of the screened patients were eligible for inclusion in the study; of these, 94% (64 of 68) underwent a bone marrow harvest or sham procedure (extended safety set) and 79% (54 of 68) were treated (study group: 25 patients; control group: 29). Forty-nine patients were included in the efficacy analyses. Similar proportions of patients in each group completed the study at 24 months of follow-up (study group: 44% [11 of 25]; control: 41% [12 of 29]). The study and control groups were comparable in important ways; for example, in the study and control groups, most patients were men (79% [27 of 34] and 87% [26 of 30], respectively) and had ARCO Stage II ONFH (76% [19 of 25] and 83% [24 of 29], respectively); the mean age was 46 and 45 years in the study and control groups, respectively. The follow-up period was 24 months post-treatment. The primary efficacy endpoint was the composite treatment response at 24 months, comprising the clinical response (clinically important improvement in pain from baseline using the WOMAC VA3.1 pain subscale, defined as 10 mm on a 100-mm scale) and radiologic response (the absence of progression to fracture stage [≥ ARCO Stage III], as assessed by conventional radiography and MRI of the hips). Secondary efficacy endpoints included the percentages of patients achieving a composite treatment response, clinical response, and radiologic response at 12 months, and the percentage of patients undergoing THA at 24 months. We maintained a continuous reporting system for adverse events and serious adverse events related to the study treatment, bone marrow aspiration and sham procedure, or other study procedures throughout the study. A planned, unblinded interim analysis of efficacy and adverse events was completed at 12 months. The study was discontinued because our data safety monitoring board recommended terminating the study for futility based on preselected futility stopping rules: conditional power below 0.20 and p = 0.01 to detect an effect size of 10 mm on the 100-mm WOMAC VA3.1 pain subscale (improvement in pain) and the absence of progression to fracture (≥ ARCO Stage III) observed on radiologic assessment, reflecting the unlikelihood that statistically beneficial results would be reached at 24 months after the treatment. RESULTS: There was no difference between the study and control groups in the proportion of patients who achieved a composite treatment response at 24 months (61% [14 of 23] versus 69% [18 of 26]; p = 0.54). There was no difference in the proportion of patients with a treatment response at 12 months between the study and control groups (14 of 21 versus 15 of 23; p = 0.92), clinical response (17 of 21 versus 16 of 23; p = 0.38), and radiologic response (16 of 21 versus 18 of 23; p = 0.87). With the numbers available, at 24 months, there was no difference in the proportion of patients who underwent THA between the study and control groups (24% [six of 25] versus 14% [four of 29]). There were no serious adverse events related to the study treatment, and only one serious adverse event (procedural pain in the study group) was related to bone marrow aspiration. Nonserious adverse events related to the treatment were rare in the study and control groups (4% [one of 25] versus 14% [four of 29]). Nonserious adverse events related to bone marrow or sham aspiration were reported by 15% (five of 34) of patients in the study group and 7% (two of 30) of patients in the control group. CONCLUSION: Our study did not show any advantage of autologous osteoblastic cells to improve the results of core decompression in early-stage (precollapse) ONFH. Adverse events related to treatment were rare and generally mild in both groups, although there might have been a potential risk associated with cell expansion. Based on our findings, we do not recommend the combination of osteoblastic cells and core decompression in patients with early-stage ONFH. Further, well-designed studies should be conducted to explore whether other treatment modalities involving a biological approach could improve the overall results of core decompression. LEVEL OF EVIDENCE: Level II, therapeutic study.

Human carbamylome description identifies carbamylated α2-macroglobulin and hemopexin as two novel autoantigens in early rheumatoid arthritis.

OBJECTIVES: Anti-carbamylated protein antibodies (anti-CarPAs) are present in RA sera and have been associated with erosive disease. The exact targets of anti-CarPAs in vivo are currently not well known; we used a proteomic approach on serum and SF of RA patients to assess the human carbamylome and to identify carbamylated autoantigens as potential biomarkers in early RA. METHODS: Mass spectrometry was performed on SF and serum from RA patients. Carbamylated proteins present in both sample types were selected as candidate autoantigens for the establishment of ELISAs. A cohort of early RA patients was tested for positivity for specific anti-CarPAs. RESULTS: Eleven novel carbamylated proteins were identified, and five were selected as potential autoantigens for detection of anti-CarPAs. Among them, antibodies against carbamylated hemopexin (anti-CaHPX) and alpha-2-macroglobulin (anti-CaA2M) showed comparable diagnostic value to the established carbamylated foetal calf serum-based ELISA. A cohort of 189 early RA patients was studied. The combination of these new biomarkers with anti-citrullinated protein antibodies and RF identified 89% of early RA patients in our cohort. There was little correlation between the tested biomarkers, and each one of the tested antigens could identify a different subset of seronegative RA patients. Anti-CaA2M positivity showed clinical potential, being associated with higher disease disability. CONCLUSION: We highlight the detection of novel carbamylated autoantigens in vivo using a combined proteomics approach in the SF and serum of RA patients. Anti-CaHPX and anti-CaA2M are promising clinical biomarkers, especially in seronegative RA.

The 2019 Revised Version of Association Research Circulation Osseous Staging System of Osteonecrosis of the Femoral Head.

BACKGROUND: The Association Research Circulation Osseous (ARCO) presents the 2019 revised staging system of osteonecrosis of the femoral head (ONFH) based on the 1994 ARCO classification. METHODS: In October 2018, ARCO established a task force to revise the staging system of ONFH. The task force involved 29 experts who used a web-based survey for international collaboration. Content validity ratios for each answer were calculated to identify the levels of agreement. For the rating queries, a consensus was defined when more than 70% of the panel members scored a 4 or 5 rating on a 5-point scale. RESULTS: Response rates were 93.1%-100%, and through the 4-round Delphi study, the 1994 ARCO classification for ONFH was successfully revised. The final consensus resulted in the following 4-staged system: stage I-X-ray is normal, but either magnetic resonance imaging or bone scan is positive; stage II-X-ray is abnormal (subtle signs of osteosclerosis, focal osteoporosis, or cystic change in the femoral head) but without any evidence of subchondral fracture, fracture in the necrotic portion, or flattening of the femoral head; stage III-fracture in the subchondral or necrotic zone as seen on X-ray or computed tomography scans. This stage is further divided into stage IIIA (early, femoral head depression ≤2 mm) and stage IIIB (late, femoral head depression >2 mm); and stage IV-X-ray evidence of osteoarthritis with accompanying joint space narrowing, acetabular changes, and/or joint destruction. This revised staging system does not incorporate the previous subclassification or quantitation parameters, but the panels agreed on the future development of a separate grading system for predicting disease progression. CONCLUSION: A staging system has been developed to revise the 1994 ARCO classification for ONFH by an expert panel-based Delphi survey. ARCO approved and recommends this revised system as a universal staging of ONFH.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 1: Glucocorticoid-Associated Osteonecrosis.

BACKGROUND: Glucocorticoid usage, a leading cause of osteonecrosis of the femoral head (ONFH), and its prevalence was reported in 25%-50% of non-traumatic ONFH patients. Nevertheless, there have been no unified criteria to classify glucocorticoid-associated ONFH (GA-ONFH). In 2015, the Association Research Circulation Osseous addressed the issue of developing a classification scheme. METHODS: In June 2017, a task force was set up to conduct a Delphi survey concerning ONFH. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey consists of questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, the panel reached a consensus on the classification criteria. The response rates were 100% (Round 1), 96% (Round 2), and 100% (Round 3), respectively. RESULTS: The consensus on the classification criteria of GA-ONFH included the following: (1) patients should have a history of glucocorticoid use >2 g of prednisolone or its equivalent within a 3-month period; (2) osteonecrosis should be diagnosed within 2 years after glucocorticoid usage, and (3) patients should not have other risk factor(s) besides glucocorticoids. CONCLUSION: Association Research Circulation Osseous established classification criteria to standardize clinical studies concerning GA-ONFH.

Etiologic Classification Criteria of ARCO on Femoral Head Osteonecrosis Part 2: Alcohol-Associated Osteonecrosis.

BACKGROUND: Although alcohol is a leading risk factor for osteonecrosis of the femoral head (ONFH) and its prevalence reportedly ranges from 20% to 45%, there are no unified classification criteria for this subpopulation. In 2015, Association Research Circulation Osseous decided to develop classification criteria for alcohol-associated ONFH. METHODS: In June of 2017, Association Research Circulation Osseous formed a task force to conduct a Delphi survey. The task force invited 28 experts in osteonecrosis/bone circulation from 8 countries. Each round of the Delphi survey included questionnaires, analysis of replies, and feedback reports to the panel. After 3 rounds of the survey, consensus was reached on the classification criteria. The response rates for the 3 Delphi rounds were 100% (round 1), 96% (round 2), and 100% (round 3). RESULTS: The consensus on the classification criteria of alcohol-associated ONFH included the following: (1) patients should have a history of alcohol intake >400 mL/wk (320 g/wk, any type of alcoholic beverage) of pure ethanol for more than 6 months; (2) ONFH should be diagnosed within 1 year after alcohol intake of this dose; and (3) patients should not have other risk factor(s). CONCLUSION: ARCO-established classification criteria to standardize clinical studies concerning AA-ONFH.

Inefficacy of autologous bone marrow concentrate in stage three osteonecrosis: a randomized controlled double-blind trial.

PURPOSE: The fracture stage of non-traumatic osteonecrosis (ON stage 3) of the femoral head (ONFH) has an unfavourable prognosis frequently requiring total hip replacement (THR). The percentage could be lowered after core decompression. In earlier non-fracture ON stages, implantation of autologous bone marrow aspirate concentrate (BMAC) improved the effect of core decompression. The purpose was to evaluate the effect of BMAC in addition to core decompression in stage 3 ONFH. METHODS: A double blind RCT was conducted comparing two groups: core decompression plus saline injection or core decompression plus BMAC implantation. Both patients and assessors were blinded to the treatment assignments. Evaluations were done at baseline, three, six, 12, and 24 months, including pain (VAS), WOMAC, side-effects, radiological evolution including ARCO subclassifications, together with possible THR requirement. The primary endpoint was the need for THR. The second endpoints included the clinical symptoms such as pain and functional ability and the progression of the ON lesions as well as the appearance of osteoarthritis features (ARCO stage 4). Both groups included 23 hips (19 patients). RESULTS: No differences were found between the groups for THR requirements, clinical tests, and radiological evolution. In both groups, 15/23 hips needed THR. The radiological evolution of the ONFH lesions in term of location, extension, surface collapse, and dome depression was moderate in both groups and was not correlated with the need of THR. CONCLUSIONS: Implantation of BMAC after core decompression did not produce any improvement of the evolution of ONFH stage 3. Level of evidence I.

Phagocyte-specific S100A8/A9 is upregulated in primary Sjögren's syndrome and triggers the secretion of pro-inflammatory cytokines in vitro.

OBJECTIVES: To determine the role of S100A8/A9 in the pathogenesis of primary Sjögren's syndrome (pSS). METHODS: The serum levels of S100A8/A9 were determined in pSS patients and healthy controls by ELISA. The expression of S100A8/A9 in salivary glands was assessed by immunohistochemistry. The phenotype of S100A8+ and S100A9+ cells was identified using double immunofluorescence. The effects of S100A8/A9 on cytokine production by peripheral blood mononuclear cells (PBMCs) from pSS patients were determined in vitro by flow cytometry. The effects of pro-inflammatory cytokines on S100A8/A9 secretion were additionally investigated in vitro by ELISA in PBMCs from pSS patients and control subjects. RESULTS: Serum levels of S100A8/A9 were significantly increased in pSS patients compared to healthy controls. The tissular expression of S100A8 and S100A9, identified in professional phagocytes (neutrophils, monocytes and plasmacytoid dendritic cells), was increased in the salivary glands of pSS patients and correlated with focus score. In vitro, recombinant S100A8/A9 increased the production of IL-1ß, IL-6, TNF-α, IFN-γ, IL-10, IL-17A and IL-22 by PBMCs. The S100A8/A9-induced increase in TNF-α production in pSS patients was significant relative to controls. Furthermore, IL-1ß, TNF-α, IL-6, and IL-17A stimulated release of S100A8/A9 from PBMCs in pSS patients. CONCLUSIONS: S100A8/A9 is increased in pSS patients contributing to the in vitro increased production of pro-inflammatory cytokines. As such, S100A8/A9 in concert with other cytokines might contribute to the pathogenesis of pSS.

Biomarkers of inflammation and innate immunity in atrophic nonunion fracture.

BACKGROUND: Nonunion is a failure of healing following a bone fracture. Its physiopathology remains partially unclear and the discovery of new mediators could promote the understanding of bone healing. METHODS: Thirty-three atrophic nonunion (NU) patients that failed to demonstrate any radiographic improvement for 6 consecutive months were recruited for providing serum samples. Thirty-five healthy volunteers (HV) served as the control group. Proteomics studies were performed using SELDI-TOF-MS and 2D-DIGE approaches, associated or not with Proteominer® preprocessing, to highlight biomarkers specific to atrophic nonunion pathology. Peak intensities were analyzed by two statistical approaches, a nonparametric Mann-Whitney U tests (univariate approach) and a machine-learning algorithm called extra-trees (multivariate approach). Validation of highlighted biomarkers was performed by alternative approaches such as microfluidic LC-MS/MS, nephelometry, western blotting or ELISA assays. RESULTS: From the 35 HV and 33 NU crude serum samples and Proteominer® eluates, 136 spectra were collected by SELDI-TOF-MS using CM10 and IMAC-Cu(2+) ProteinChip arrays, and 665 peaks were integrated for extra-trees multivariate analysis. Accordingly, seven biomarkers and several variants were identified as potential NU biomarkers. Their levels of expression were found to be down- or up-regulated in serum of HV vs NU. These biomarkers are inter-α-trypsin inhibitor H4, hepcidin, S100A8, S100A9, glycated hemoglobin ß subunit, PACAP related peptide, complement C3 α-chain. 2D-DIGE experiment allowed to detect 14 biomarkers as being down- or up-regulated in serum of HV vs NU including a cleaved fragment of apolipoprotein A-IV, apolipoprotein E, complement C3 and C6. Several biomarkers such as hepcidin, complement C6, S100A9, apolipoprotein E, complement C3 and C4 were confirmed by an alternative approach as being up-regulated in serum of NU patients compared to HV controls. CONCLUSION: Two proteomics approaches were used to identify new biomarkers up- or down-regulated in the nonunion pathology, which are involved in bone turn-over, inflammation, innate immunity, glycation and lipid metabolisms. High expression of hepcidin or S100A8/S100A9 by myeloid cells and the presence of advanced glycation end products and complement factors could be the result of a longstanding inflammatory process. Blocking macrophage activation and/or TLR4 receptor could accelerate healing of fractured bone in at-risk patients.

Adenosine triphosphate prevents serum deprivation-induced apoptosis in human mesenchymal stem cells via activation of the MAPK signaling pathways.

Human mesenchymal stem cells (hMSC) are multipotent cells derived from various sources including adipose and placental tissues as well as bone marrow. Owing to their regenerative and immunomodulatory properties, their use as a potential therapeutic tool is being extensively tested. However, one of the major hurdles in using cell-based therapy is the use of fetal bovine serum that can trigger immune responses, viral and prion diseases. The development of a culture medium devoid of serum while preserving cell viability is therefore a major challenge. In this study, we demonstrated that adenosine triphosphate (ATP) restrained serum deprivation-induced cell death in hMSC by preventing caspases 3/7 activation and modulating ERK1/2 and p38 MAPK signaling pathways. We also showed that serum deprivation conditions triggered dephosphorylation of the proapoptotic protein Bad leading to cell death. Adjunction of ATP restored the phosphorylation state of Bad. Furthermore, ATP significantly modulated the expression of proapoptopic and antiapoptotic genes, in favor of an antiapoptotic profile expression. Finally, we established that hMSC released a high amount of ATP in the extracellular medium when cultured in a serum-free medium. Collectively, our results demonstrate that ATP favors hMSC viability in serum deprivation conditions. Moreover, they shed light on the cardinal role of the MAPK pathways, ERK1/2 and p38 MAPK, in promoting hMSC survival.

Potential involvement of the IL-33-ST2 axis in the pathogenesis of primary Sjogren's syndrome.

OBJECTIVES: To investigate the role of the interleukin (IL)-33-ST2 axis in the pathophysiology of primary Sjögren's syndrome (pSS). METHODS: Serum levels of IL-33 and sST2 were determined by ELISA. The expression of IL-33 and ST2 was investigated in salivary glands (SG) by immunohistochemistry. PBMC were isolated and stimulated with IL-33, IL-12 and IL-23 and the cytokine profile response was examined by flow cytometry. Intracellular cytokine detection of IFNγ and IL-17 was performed by flow cytometry. RESULTS: Serum IL-33 and sST2 levels were increased in pSS patients compared with controls and patients with systemic lupus erythematosus. Expression of IL-33 was upregulated in SG with Chisholm scores of 2 and 3 of pSS patients but comparable with controls for SG with Chisholm score of 4. ST2 expression in SG was downregulated in pSS patients. IL-33 at different concentrations did not increase the secretion of pro-inflammatory cytokines but acted synergistically with IL-12 and IL-23 to promote IFNγ production. NK and NKT cells were identified as main producers of IFNγ in vitro and were found in SG of pSS patients. CONCLUSIONS: IL-33 is released in pSS, and acts with IL-12 and IL-23 to favour the secretion of IFNγ by NK and NKT cells.

Cryofibrinogen levels are increased in non-traumatic osteonecrosis: a new pathogenic clue to osteonecrosis?

OBJECTIVE: To determine whether levels of cryofibrinogen are increased in non-traumatic osteonecrosis (ON) and could correlate with disease staging. METHODS: We prospectively analysed cryofibrinogen levels by immunofixation electrophoresis in 50 patients with non-traumatic ON, 50 healthy volunteers and 8 patients with traumatic ON. Staging of disease involving the femoral heads and the size of necrotic lesions were assessed by the Association Research Circulation Osseous (ARCO) classification system. RESULTS: Mean cryofibrinogen levels in patients with non-traumatic ON were significantly increased relative to healthy controls and to patients with traumatic ON (222.1 ± 20.6, 59.9 ± 5.6 and 52.3 ± 14.9 mg/dl, respectively, P < 0.001). In the non-traumatic ON group, mean cryofibrinogen levels were significantly increased in patients with multifocal ON compared with patients with mono/bifocal ON (276.5 ± 56.5 and 149.3 ± 15.4 mg/dl, respectively, P = 0.03). There were no significant differences in cryofibrinogen levels observed with respect to the size of the necrotic lesions involving the femoral heads. Moreover, cryofibrinogen levels in patients with ON of the femoral heads classified according to the stage of disease were not significantly different between patients with stage 1/2 and patients with stage 3 ON (179.2 ± 31.3 vs 204.1 ± 29.0 mg/dl, respectively; P = 0.813). CONCLUSION: Cryofibrinogen levels are increased in non-traumatic ON and, more importantly, in multifocal ON. The fact that cryofibrinogen levels are not correlated with the size of lesions and the stage of disease could imply systemic rather than local involvement characterizing the pathogenesis of ON.

Inefficacy of the cementation of femoral head collapse in glucocorticoid-induced osteonecrosis.

The objective of this paper was to assess the efficacy of cementation of the femoral head in stage III glucocorticoid-induced osteonecrosis. Ten hips (nine patients) were treated by the injection of low-viscosity cement to reduce the collapse. The follow up included clinical and radiological assessments preoperatively and at 3, 6 and 12 months after surgery. The visual analogue scale (VAS) score, the Lequesne index and the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) score did not show any significant improvement. Eight of the ten hips showed a worsening of the collapse and required total hip arthroplasty during follow up. The mean time before total hip replacement was 8.6 +/- 7 months. The other two hips did not show any relapse of collapse nor functional worsening at the maximum follow up of 5 years. Our results suggest that cement injection is not a treatment that should be proposed for glucocorticoid-induced osteonecrosis.

Induction of Stearoyl-CoA 9-Desaturase 1 Protects Human Mesenchymal Stromal Cells Against Palmitic Acid-Induced Lipotoxicity and Inflammation.

In bone diseases such as osteonecrosis and osteoporosis, a shift toward a preferential differentiation of mesenchymal stromal cells (MSC) into adipocytes at the expense of the osteoblastic lineage is described, leading to excessive accumulation of adipocytes in the bone marrow of the patients. The influence of cytokines and adipokines secreted by adipocytes on skeletal health is already well-documented but the impact of free fatty acids release on bone cell biology and viability is an emerging concept. We have previously demonstrated that the saturated fatty acid (SFA) palmitate (Palm) is cytotoxic for human MSC (hMSC) and osteoblasts whereas oleate (Ole), a monounsaturated fatty acid (MUFA), has no toxic effect. Moreover, Ole protects cells against lipotoxicity. Our observations led us to propose that the toxicity of the SFA is not correlated to its intracellular accumulation but could rather be related to the intracellular SFA/MUFA ratio, which finally determines the toxic effect of SFA. Therefore, in the present study, we have investigated the potential protective role of the enzyme stearoyl-CoA 9-desaturase 1 (SCD1) against the deleterious effects of Palm. SCD1 is an enzyme responsible for desaturation of SFA to MUFA; its activation could therefore lead to modifications of the intracellular SFA/MUFA ratio. In the present study, we showed that hMSC express SCD1 and liver X receptors (LXRs), transcription factors regulating SCD1 expression. Human MSC treatment with a LXRs agonist triggered SCD1 expression and drastically reduced Palm-induced cell mortality, caspases 3/7 activation, endoplasmic reticulum stress and inflammation. We also observed that, in the presence of Palm, the LXRs agonist provoked lipid droplets formation, augmented the total cellular neutral lipid content but decreased the SFA/MUFA ratio when compared to Palm treatment alone. Addition of an inhibitor of SCD1 activity abrogated the positive effects of the LXRs agonist, suggesting that SCD1 could play a key role in protecting hMSC against lipotoxicity.

Non traumatic osteonecrosis of the femoral head is associated with low bone mass.

OBJECTIVE: Osteoporosis (OP) and osteonecrosis of the femoral head (ONFH) share common clinical and pathophysiological features we sought to determine whether ONFH was associated with an increased prevalence of OP and whether the increased prevalence of OP was related to the stage of ONFH at diagnosis. METHODS: We included 243 patients with ONFH and 399 age and sex-matched healthy controls. Data was gathered including demography, risk factors, ARCO staging of ONFH and bone mineral density (BMD). RESULTS: Overall, BMD (defined by the T-score) was significantly lower in the ONFH group at both the femoral head (-0.96±1.11) and the lumbar spine (-1.22±1.47) compared to the control group (-0.55±0.97 and -0.73±1.31) (p<0.01). The ONFH group depicted a significantly higher proportion of osteopenia (50.39% vs 40.87%, p=0.027) and of OP (18.78% vs 7.33%, p<0.001) relative to the control group. Stage 1 and 2 ONFH patients (53.86%, p=0.0203; OR=1.54 (95% CI: [1.04; 2.29])) were at a higher risk of osteopenia than the control group (40.88%), but not stages 3 or 4 (48.47%, p=0.2569; OR=1.27 (95% CI: [0.78; 2.06]). Patients with stage 3 or 4 ONFH (25.31%, p<0.001; OR=3.93 (95% CI: [1.63; 10.96])) were at a higher risk of osteoporosis than patients in the stage 1 and 2 ONFH (7.24%), and compared to the control group (7.33%, adj. p-value<0.001; OR=4.89 (95% CI: [2.77; 8.76]). CONCLUSIONS: Non-traumatic osteonecrosis of the femoral heads is associated with low bone mineral density. This study showed that fractural stages ONFH were associated with a 5-fold risk of osteoporosis.

High Prevalence of Undiagnosed Axial Spondyloarthritis in Patients with Chronic Low Back Pain Consulting Non-Rheumatologist Specialists in Belgium: SUSPECT Study.

INTRODUCTION: Diagnosis of axial spondyloarthritis (SpA) can be delayed for several years mainly because of low awareness of axial SpA among non-rheumatologists who are the first interlocutors of potential SpA patients. One strategy to decrease the delay between appearance of first symptoms and diagnosis of axial SpA and to allow early management of the disease is to provide the non-rheumatologists with tools to identify patients requiring prompt referral to rheumatologists. This study was designed to evaluate in a real-world setting whether screening patients with chronic low back pain who consult physical medicine and rehabilitation (PMR) physicians, orthopedists, and ophthalmologists is useful in detecting axial SpA. METHODS: During this non-interventional cross-sectional study, data from 161 patients with chronic back pain, consulting an orthopedist, PMR physician, or ophthalmologist were collected during a single visit. Any patient who presented with at least four out of five symptoms of inflammatory back pain (IBP) and at least one additional SpA feature were to be referred to a rheumatologist. Analysis was purely descriptive. RESULTS: IBP was diagnosed in approximately half of the patients (89 patients) and 72 of them met the referral criteria. A total of 117 patients were finally referred to a rheumatologist and axial SpA was diagnosed for 37 of them. CONCLUSIONS: The high prevalence of undiagnosed axial SpA in patients with chronic back pain visiting PMR physicians, orthopedists, and ophthalmologists suggests that these healthcare professionals may play a key role in the strategy developed to shorten the delay observed in the formal diagnosis of SpA. FUNDING: Abbvie.

Value of non-identified ANCA (non-PR3, non-MPO) in the diagnosis of granulomatosis with polyangiitis (Wegener's granulomatosis).

OBJECTIVE: Determine the frequency of granulomatosis with polyangiitis (GPA) associated with non-identified ANCA (non-MPO, non-PR3 ANCA) and secondarily compare their clinic with GPA associated with MPO-positive or PR3-positive ANCA. METHODS: In a monocentric retrospective observational study, clinical data of 398 patients with non-identified ANCA (titer of ANCA at least 1/80 by immunofluorescence on ethanol fixed PMN) was gathered over a period of 6 years. GPA patients from this population were compared with GPA patients with identified ANCA on the basis of clinical, biological, immunological and histological features. RESULTS: The most common diseases associated with non-identified ANCA were inflammatory bowel diseases accounting for 17% of diseases. GPA accounted for only 1.8% of cases. There were no significant differences in terms of clinical and histological characteristics between GPA with non-identified ANCA and GPA with identified ANCA, but significantly higher CRP levels were observed in GPA patients with identified ANCA (p = 0.005). Localized disease (ear, nose and throat and/or lung involvement without any other systemic involvement) was more frequent in the group of GPA with nonidentified ANCA (p = 0.047) as compared to GPA with identified ANCA. This explains that the former group of patients was less frequently treated by cyclophosphamide than the latter (p = 0.016). CONCLUSION: GPA with non-MPO, non-PR3 ANCAs is relatively rare. Our study suggests that GPA with nonidentified ANCA differs from GPA with identified ANCA by the frequency of localized forms.

Osteonecrosis of the Femoral Head: Lipotoxicity Exacerbation in MSC and Modifications of the Bone Marrow Fluid.

Osteonecrosis of the femoral head (ON) is a multifactorial bone disease that can evolve to a progressive destruction of the hip joint. Different pathogenic processes have been proposed, among them, an increase of bone marrow (BM) fat resulting from adipocyte accumulation. Marrow adipocytes are active BM residents that influence the microenvironment by releasing cytokines, adipokines, and free fatty acids (FA). We explored the impact of palmitate (Palm) and oleate on function and survival of BM-derived mesenchymal stromal cells (MSC) of osteonecrotic patients (ONMSC) and healthy volunteers. Moreover, we analyzed the FA profile of the serum and the BM supernatant fluid (BMSF). We demonstrated that exposure to the saturated FA Palm favored MSC differentiation through the adipogenic lineage at the expense of the osteoblastic phenotype. Moreover, adipogenesis was intensified in ONMSC. The susceptibility to Palm toxicity was aggravated in ONMSC concomitantly with a greater activation of the proapoptotic extracellular signal-regulated kinase pathway. Moreover, cellular mechanisms implicated in the protection against lipotoxicity, such as stearoyl-coenzyme A desaturase 1 and carnitine palmitoyl transferase 1 expression, were dysregulated in ONMSC. Palm-induced interleukin (IL)-6 and IL-8 secretion was also exacerbated in ONMSC. Our results established that, in the serum, the FA profiles were comparable in ON and healthy subjects. However, both the concentrations and the FA composition were modified in the BMSF of ON patients, highlighting a drastic change of the BM microenvironment in ON patients. Altogether, our work suggests that marrow adipocyte enlargement could affect the process of bone remodeling and, therefore, play a role in the pathogenesis of ON.

Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. Surgical technique.

BACKGROUND: Aseptic nontraumatic osteonecrosis of the femoral head is a disorder that can lead to femoral head collapse and the need for total hip replacement. Since osteonecrosis may be a disease of mesenchymal cells or bone cells, the possibility has been raised that bone marrow containing osteogenic precursors implanted into a necrotic lesion of the femoral head may be of benefit in the treatment of this condition. For this reason, we studied the implantation of autologous bone-marrow mononuclear cells in a necrotic lesion of the femoral head to determine the effect on the clinical symptoms and the stage and volume of osteonecrosis. METHODS: We studied thirteen patients (eighteen hips) with stage-I or II osteonecrosis of the femoral head, according to the system of the Association Research Circulation Osseous. The hips were allocated to a program of either core decompression (the control group) or core decompression and implantation of autologous bone-marrow mononuclear cells (the bone-marrow-graft group). Both patients and assessors were blind with respect to treatment-group assignment. The primary outcomes studied were safety, clinical symptoms, and disease progression. RESULTS: After twenty-four months, there was a significant reduction in pain (p = 0.021) and in joint symptoms measured with the Lequesne index (p = 0.001) and the WOMAC index (p = 0.013) within the bone-marrow-graft group. At twenty-four months, five of the eight hips in the control group had deteriorated to stage III, whereas only one of the ten hips in the bone-marrow-graft group had progressed to this stage. Survival analysis showed a significant difference in the time to collapse between the two groups (p = 0.016). Implantation of bone-marrow mononuclear cells was associated with only minor side effects. CONCLUSIONS: Implantation of autologous bone-marrow mononuclear cells appears to be a safe and effective treatment for early stages of osteonecrosis of the femoral head. Although the findings of this study are promising, their interpretation is limited because of the small number of patients and the short duration of follow-up. Further study is needed to confirm the results.