The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis:Results from Daily Clinical Practice

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0–72), cervical facet joint involvement according the “de Vlam” scoring method (0–15) and radiographic vertebral fractures (VF) using the “Genant” method (grade 0–3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender.Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0–2 year change in Z-scores of +0.1, −0.4, and −1.2, respectively.Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.</p

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis:Results from Daily Clinical Practice

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0–72), cervical facet joint involvement according the “de Vlam” scoring method (0–15) and radiographic vertebral fractures (VF) using the “Genant” method (grade 0–3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender.Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0–2 year change in Z-scores of +0.1, −0.4, and −1.2, respectively.Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.</p

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis:Results from Daily Clinical Practice

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0–72), cervical facet joint involvement according the “de Vlam” scoring method (0–15) and radiographic vertebral fractures (VF) using the “Genant” method (grade 0–3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender.Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0–2 year change in Z-scores of +0.1, −0.4, and −1.2, respectively.Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.</p

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis:Results from Daily Clinical Practice

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0–72), cervical facet joint involvement according the “de Vlam” scoring method (0–15) and radiographic vertebral fractures (VF) using the “Genant” method (grade 0–3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender.Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0–2 year change in Z-scores of +0.1, −0.4, and −1.2, respectively.Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.</p

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis:Results from Daily Clinical Practice

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0–72), cervical facet joint involvement according the “de Vlam” scoring method (0–15) and radiographic vertebral fractures (VF) using the “Genant” method (grade 0–3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender.Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0–2 year change in Z-scores of +0.1, −0.4, and −1.2, respectively.Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.</p

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis:Results from Daily Clinical Practice

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0–72), cervical facet joint involvement according the “de Vlam” scoring method (0–15) and radiographic vertebral fractures (VF) using the “Genant” method (grade 0–3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender.Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0–2 year change in Z-scores of +0.1, −0.4, and −1.2, respectively.Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.</p

Baseline serum biomarkers of inflammation, bone turnover and adipokines predict spinal radiographic progression in ankylosing spondylitis patients on TNF inhibitor therapy

Objective: To analyze whether biomarker levels at baseline or their change after 3 months or 2 years predict radiographic spinal progression in ankylosing spondylitis (AS) patients treated with TNF-α inhibitors (TNFi). Methods: 137 AS patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were included before starting TNFi. Serum biomarkers were measured at baseline, 3 months and 2 years: Markers of inflammation (calprotectin, matrix metalloproteinase-3, vascular endothelial growth factor), bone turnover markers (bone-specific alkaline phosphatase, serum C-terminal telopeptide fragments of type I collagen (sCTX), osteocalcin, osteoprotegerin, procollagen type I and II N-terminal propeptide, sclerostin) and adipokines (high-molecular-weight adiponectin, leptin, visfatin). Spinal radiographs were scored at baseline, 2 and 4 years. Logistic regression was performed to examine the association between biomarker values and radiographic spinal progression, adjusting for known risk factors for radiographic progression. Results: Baseline calprotectin and visfatin levels were associated with mSASSS progression ≥2 points (OR 1.195 [95%CI 1.055–1.355] and 1.465 [1.137–1.889], respectively), while calprotectin was also associated with new syndesmophyte formation after 2 years (OR 1.107 [1.001–1.225]). Baseline leptin level was associated with mSASSS progression ≥4 points after 4 years (OR 0.614 [0.453–0.832]), and baseline sCTX level with syndesmophyte formation after 4 years (OR 1.004 [1.001–1.008]). Furthermore, change of visfatin and leptin levels over the first 2 years showed significant association with radiographic progression after 4 years. Conclusion: Independent of known risk factors, serum levels of biomarkers at baseline are able to predict radiographic spinal progression over 2 and 4 years in AS patients on TNFi therapy

Immune response to varicella-zoster virus before and after renal transplantation

Background: Herpes zoster (HZ) risk is high in renal transplant recipients. Vaccination prior to transplantation may provide a useful strategy for the prevention of HZ in the posttranplantation period. However, it is not known whether immunity to varicella-zoster virus (VZV) is affected due to treatment surrounding transplantation. Methods: Both humoral and cellular immunity to VZV were determined prior to and 2-3 years after renal transplantation in 60 adult patients, and 62 matched healthy controls. VZV-specific cellular immunity was measured by an interferon gamma (IFN gamma) enzyme-linked immunospot (ELISpot) assay and by analyzing T-cell functionality using flowcytometry. VZV-IgG levels were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (gpELISA). Results: Using paired analysis, it was determined that numbers of IFN gamma-producing cells did not change after transplantation, but were significantly lower in transplant recipients after transplantation than in controls (p = 0.028). Patients in whom the post-transplant period was complicated by rejection or any acute infection (excluding HZ) had a lower number of IFN gamma-producing cells than patients who did not. VZV IgG levels did not differ from controls, but a significant decrease was observed after transplantation (p <0.0001). Conclusions: VZV-specific cellular immunity, which is essential in the prevention of HZ, did not markedly change in patients following renal transplantation. This suggests that preventive vaccination before transplantation may be beneficial. Our results extend knowledge on VZV immunity after transplantation, vital when considering strategies for the prevention of HZ in these patients

Massive multiplication of genome and ribosomes in dormant cells (akinetes) of Aphanizomenon ovalisporum (Cyanobacteria)

Author Posting. © The Author(s), 2011. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in The ISME Journal 6 (2012): 670–679, doi:10.1038/ismej.2011.128.Akinetes are dormancy cells commonly found among filamentous cyanobacteria, many of which are toxic and/or nuisance, bloom-forming species. Development of akinetes from vegetative cells is a process that involves morphological and biochemical modifications. Here we applied a single cell approach to quantify genome and ribosome content of akinetes and vegetative cells in Aphanizomenon ovalisporum (Cyanobacteria). Vegetative cells of A. ovalisporum were naturally polyploid and contained on average 8 genome copies per cell. However, the chromosomal content of akinetes increased up to 450 copies, with an average value of 119 genome copies per akinete, 15 fold higher that in vegetative cells. Based on fluorescence in situ hybridization with a probe targeting 16S rRNA and detection with confocal laser scanning microscopy we conclude that ribosomes accumulated in akinetes to a higher level than that found in vegetative cells. We further present evidence that this massive accumulation of nucleic acids in akinetes is likely supported by phosphate supplied from inorganic polyphosphate bodies that were abundantly present in vegetative cells, but notably absent from akinetes. These results are interpreted in the context of cellular investments for proliferation following long term dormancy, as the high nucleic acid content would provide the basis for extended survival, rapid resumption of metabolic activity and cell division upon germination.Supported by the Gruss Lipper Foundation research award (AS). This study was part of the Joint German-Israeli-Project (FKZ 02WT0985, WR803) funded by the German Ministry of Research and Technology (BMBF) and Israel Ministry of Science and Technology (MOST)

Serum levels of bone turnover markers including calculation of Z-scores:Data from a Dutch healthy reference cohort

Introduction: Bone turnover markers (BTM) are biochemical compounds reflecting different stages of bone metabolism. Their levels change with age and differ between males and females. This makes clinical interpretation and comparison more difficult. Therefore, our aim was to establish BTM reference values which can be used to calculate Z-scores for use in daily clinical practice.Methods: Serum markers of collagen resorption, bone formation/regulation, collagen formation and bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured in non-fasting volunteers without bone-related abnormalities. Raw data was plotted and gender-specific age cohorts were established with their respective means and standard deviations (SD). Z-scores can be calculated using these reference values to correct for the influence of age and gender on BTM.Results: In total, 856 individuals were included of which 486 (57 %) were female. Individuals were aged between 7 and 70 years. Highest serum levels of BTM were found in childhood and puberty. Peak levels are higher in boys than girls and prevail at later ages. In adults, BTM levels decrease before reaching stable nadir levels. In adults, 10-year reference cohorts with means and SD were provided to calculate Z-scores.Conclusion: With our data, Z-scores of sCTX, OC, PINP and BALP can be calculated using reference categories (for age and gender) of Caucasian healthy volunteers. Clinicians can use BTM Z-scores to determine whether there are changes in bone turnover physiology beyond those expected during aging. BTM Z-scores facilitate harmonization of data interpretation in daily clinical practice and research.</p