Delivering rhFGF-18 via a bilayer collagen membrane to enhance microfracture treatment of chondral defects in a large animal model.

Augmented microfracture techniques use growth factors, cells, and/or scaffolds to enhance the healing of microfracture-treated cartilage defects. This study investigates the effect of delivering recombinant human fibroblastic growth factor 18 (rhFHF18, Sprifermin) via a collagen membrane on the healing of a chondral defect treated with microfracture in an ovine model. Eight millimeter diameter chondral defects were created in the medial femoral condyle of 40 sheep (n = 5/treatment group). Defects were treated with microfracture alone, microfracture + intra-articular rhFGF-18 or microfracture + rhFGF-18 delivered on a membrane. Outcome measures included mechanical testing, weight bearing, International Cartilage Repair Society repair score, modified O'Driscoll score, qualitative histology, and immunohistochemistry for types I and II collagen. In animals treated with 32 μg rhFGF-18 + membrane and intra-articularly, there was a statistically significant improvement in weight bearing at 2 and 4 weeks post surgery and in the modified O'Driscoll score compared to controls. In addition, repair tissue stained was more strongly stained for type II collagen than for type I collagen. rhFGF-18 delivered via a collagen membrane at the point of surgery potentiates the healing of a microfracture treated cartilage defect.This is the author accepted manuscript. The final version is available via Wiley at http://onlinelibrary.wiley.com/doi/10.1002/jor.22882/abstract

Characterisation of the safety profile of evobrutinib in over 1000 patients from phase II clinical trials in multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus: an integrated safety analysis

Immunology; Multiple sclerosis; RheumatologyInmunología; Esclerosis múltiple; ReumatologíaImmunologia; Esclerosi múltiple; ReumatologiaObjective Analyse the integrated safety profile of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi), using pooled data from multiple sclerosis (MS), rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) trials. Methods Phase II, randomised, double-blind, placebo-controlled trial data were analysed (N=1083; MS: n=213, 48 weeks (W); RA: n=390, 12W; SLE: n=480, 52W). The analysis included all patients who received ≥1 dose of evobrutinib (25 mg or 75 mg once daily, or 50 mg or 75 mgtwice daily) or placebo. Descriptive statistics and exposure-adjusted incidence rates (EAIR) were used to report treatment-emergent adverse events (TEAEs). Results Data from 1083 patients were pooled: evobrutinib, n=861; placebo, n=271 (sum >1083 due to MS trial design: n=49 received both placebo (W0–24) and evobrutinib 25 mg (W25–48)); median follow-up time (pt-years): evobrutinib, 0.501; placebo, 0.463. Across indications, the proportion of patients with TEAEs and the EAIR were similar for evobrutinib and placebo (66.2% (247.6 events/100 pt-years) vs 62.4% (261.4 events/100 pt-years)). By indication, the EAIR (events/100 pt-years) of TEAEs for evobrutinib versus placebo were: MS: 119.7 vs 148.3; RA: 331.8 vs 306.8; SLE: 343.0 vs 302.1. Two fatal events occurred (in SLE). The serious infections EAIR was 2.7 and 2.1 events/100 pt-years for evobrutinib and placebo. For previously reported BTKi-class effects, the EAIR of transient elevated alanine aminotransferase/aspartate aminotransferase TEAEs (events/100 pt-years) with evobrutinib versus placebo was 4.8 vs 2.8/3.5 vs 0.7, respectively. IgG levels were similar in evobrutinib/placebo-treated patients. Conclusions This is the first BTKi-integrated safety analysis that includes patients with MS. Overall, evobrutinib treatment (all doses) was generally well tolerated across indications.The trial was sponsored by Merck Healthcare KGaA (CrossRef Funder ID: 10.13039/100009945)

Osteochondral tissue engineering using a biphasic collagen/GAG scaffold containing rhFGF18 or BMP-7 in an ovine model.

BACKGROUND: The aim of this study was to investigate the effect of combining rhFGF18 or BMP-7 with a biphasic collagen/GAG osteochondral scaffold (Chondromimetic) on the repair of osteochondral defects in sheep. METHODS: Osteochondral defects (5.8x6mm) were created in the medial femoral condyle (MFC) and the lateral trochlea sulcus (LTS) of the stifle joint of 24 female sheep. Sheep were randomly assigned to four groups (n = 6); 1) empty defect, 2) scaffold only, 3) scaffold + rhFGF-18 (30 μg) and 4) scaffold + BMP-7 (100 μg). At 6 months the defects underwent non-destructive mechanical testing, gross assessment of repair tissue (ICRS score) and histological analysis (Modified O'Driscoll score). RESULTS: ICRS repair score: Defects treated with scaffold + rhFGF18 (mean 9.83, 95% CI 8.43-11.23) and scaffold + BMP-7 (10, 9.06-10.94) in the MFC had significantly improved ICRS scores compared to empty defects (4.2, 0-8.80) (p = 0.002). Mechanical properties: BMP-7 treated defects (mean 64.35, 95% CI 56.88-71.82) were significantly less stiff than both the rhFGF18 (mean 84.1, 95% CI 76.8-91.4) and empty defects in the LTS, compared to both contralateral limb (p = 0.003), and the perilesional articular cartilage (p < 0.001). HISTOLOGY: A statistically significant improvement in the modified O'Driscoll score was observed in the rhFGF18 treated group (mean 16.83, 95% CI 13.65-20.61) compared to the empty defects (mean 9, 95% CI 4.88-13.12) (p = 0.039) in the MFC. Excellent tissue fill, lateral integration and proteoglycan staining was observed. Only the rhFGF18 defects showed pericellular type VI collagen staining with positive type II collagen and reduced positive type I collagen staining. The majority of defects in the control and BMP-7 groups demonstrated fibrocartilagenous repair tissue. CONCLUSION: Statistically significant improvements in gross repair, mechanical properties and histological score were found over empty defects when Chondromimetic was combined with rhFGF18. These results suggest that rhFGF18 may play a significant role in articular cartilage repair applications.This is the final published version. It is published by Springer in the Journal of Experimental Orthopaedics here: http://www.jeo-esska.com/content/1/1/13

Relationship Between Motion, Using the GaitSmartTM System, and Radiographic Knee Osteoarthritis: An Explorative Analysis in the IMI-APPROACH Cohort

Multicenter study[Abstract] Objectives: To assess underlying domains measured by GaitSmartTMparameters and whether these are additional to established OA markers including patient reported outcome measures (PROMs) and radiographic parameters, and to evaluate if GaitSmart analysis is related to the presence and severity of radiographic knee OA. Methods: GaitSmart analysis was performed during baseline visits of participants of the APPROACH cohort (n = 297). Principal component analyses (PCA) were performed to explore structure in relationships between GaitSmart parameters alone and in addition to radiographic parameters and PROMs. Logistic and linear regression analyses were performed to analyse the relationship of GaitSmart with the presence (Kellgren and Lawrence grade ≥2 in at least one knee) and severity of radiographic OA (ROA). Results: Two hundred and eighty-four successful GaitSmart analyses were performed. The PCA identified five underlying GaitSmart domains. Radiographic parameters and PROMs formed additional domains indicating that GaitSmart largely measures separate concepts. Several GaitSmart domains were related to the presence of ROA as well as the severity of joint damage in addition to demographics and PROMs with an area under the receiver operating characteristic curve of 0.724 and explained variances (adjusted R2) of 0.107, 0.132 and 0.147 for minimum joint space width, osteophyte area and mean subchondral bone density, respectively. Conclusions: GaitSmart analysis provides additional information over established OA outcomes. GaitSmart parameters are also associated with the presence of ROA and extent of radiographic severity over demographics and PROMS. These results indicate that GaitsmartTM may be an additional outcome measure for the evaluation of OA

99mTc-NTP 15-5 is a companion radiotracer for assessing joint functional response to sprifermin (rhFGF-18) in a murine osteoarthritis model

International audienceAbstract With the emergence of disease modifying osteoarthritis drugs (DMOAD), imaging methods to quantitatively demonstrate their efficacy and to monitor osteoarthritis progression at the functional level are urgently needed. Our group showed that articular cartilage can be quantitatively assessed in nuclear medicine imaging by our radiotracer 99m Tc-NTP 15-5 targeting cartilage proteoglycans. In this work, surgically induced DMM mice were treated with sprifermin or saline. We investigated cartilage remodelling in the mice knees by 99m Tc-NTP 15-5 SPECT-CT imaging over 24 weeks after surgery, as wells as proteoglycan biochemical assays. OA alterations were scored by histology according to OARSI guidelines. A specific accumulation of 99m Tc-NTP 15-5 in cartilage joints was evidenced in vivo by SPECT-CT imaging as early as 30 min post-iv injection. In DMM, 99m Tc-NTP 15-5 accumulation in cartilage within the operated joints, relative to contralateral ones, was observed to initially increase then decrease as pathology progressed. Under sprifermin, 99m Tc-NTP 15-5 uptake in pathological knees was significantly increased compared to controls, at 7-, 12- and 24-weeks, and consistent with proteoglycan increase measured 5 weeks post-surgery, as a sign of cartilage matrix remodelling. Our work highlights the potential of 99m Tc-NTP 15-5 as an imaging-based companion to monitor cartilage remodelling in OA and DMOAD response

Relationship between motion, using the GaitSmartTM system, and radiographic knee osteoarthritis: an explorative analysis in the IMI-APPROACH cohort

International audienceObjectives. To assess underlying domains measured by GaitSmart TM parameters and whether these are additional to established OA markers including patient reported outcome measures (PROMs) and radiographic parameters, and to evaluate if GaitSmart analysis is related to the presence and severity of radiographic knee OA. Methods. GaitSmart analysis was performed during baseline visits of participants of the APPROACH cohort (n ¼ 297). Principal component analyses (PCA) were performed to explore structure in relationships between GaitSmart parameters alone and in addition to radiographic parameters and PROMs. Logistic and linear regression analyses were performed to analyse the relationship of GaitSmart with the presence (Kellgren and Lawrence grade !2 in at least one knee) and severity of radiographic OA (ROA). Results. Two hundred and eighty-four successful GaitSmart analyses were performed. The PCA identified five underlying GaitSmart domains. Radiographic parameters and PROMs formed additional domains indicating that GaitSmart largely measures separate concepts. Several GaitSmart domains were related to the presence of ROA as well as the severity of joint damage in addition to demographics and PROMs with an area under the receiver operating characteristic curve of 0.724 and explained variances (adjusted R 2) of 0.107, 0.132 and 0.147 for minimum joint space width, osteophyte area and mean subchondral bone density, respectively. Conclusions. GaitSmart analysis provides additional information over established OA outcomes. GaitSmart parameters are also associated with the presence of ROA and extent of radiographic severity over demographics and PROMS. These results indicate that Gaitsmart TM may be an additional outcome measure for the evaluation of OA

sj-docx-1-msj-10.1177_13524585241234783 – Supplemental material for Efficacy and safety results after >3.5 years of treatment with the Bruton’s tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study

Supplemental material, sj-docx-1-msj-10.1177_13524585241234783 for Efficacy and safety results after >3.5 years of treatment with the Bruton’s tyrosine kinase inhibitor evobrutinib in relapsing multiple sclerosis: Long-term follow-up of a Phase II randomised clinical trial with a cerebrospinal fluid sub-study by Xavier Montalban, Karolina Piasecka-Stryczynska, Jens Kuhle, Pascal Benkert, Douglas L Arnold, Martin S Weber, Andrea Seitzinger, Hans Guehring, Jamie Shaw, Davorka Tomic, Yann Hyvert, Danielle E Harlow, Martin Dyroff and Jerry S Wolinsky in Multiple Sclerosis Journal</p

Biomechanical effect of different lumbar interspinous implants on flexibility and intradiscal pressure

Interspinous implants are used to treat lumbar spinal stenosis or facet joint arthritis. The aims of implanting interspinous devices are to unload the facet joints, restore foraminal height and provide stability especially in extension but still allow motion. The aim of this in vitro study was to compare four different interspinous implants––Colfex, Wallis, Diam and X-Stop––in terms of their three-dimensional flexibility and the intradiscal pressure. Twenty-four human lumbar spine specimens were divided into four equal groups and tested with pure moments in flexion/extension, lateral bending and axial rotation: (1) intact, (2) defect, (3) after implantation. Range of motion and the intradiscal pressure were determined.In each implant-group the defect caused an increase in range of motion by about 8% in lateral bending to 18% in axial rotation. Implantation had similar effects with all four implants. In extension, Coflex, Wallis, Diam, and X-Stop all overcompensated the instability caused by the defect and allowed about 50% of the range of motion of the intact state. In contrast, in flexion, lateral bending and axial rotation the values of the range of motion stayed about the values of the defect state. Similarly the intradiscal pressure after implantation was similar to that of the intact specimens in flexion, lateral bending and axial rotation but much smaller during extension. All tested interspinous implants had a similar effect on the flexibility: they strongly stabilized and reduced the intradiscal pressure in extension, but had almost no effect in flexion, lateral bending and axial rotation