Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection

Treatment expectations and patient-reported outcomes of nusinersen therapy in adult spinal muscular atrophy

Background!#!The antisense-oligonucleotide (ASO) nusinersen has recently been approved as the first genetically modifying therapy for 5q-associated spinal muscular atrophy (SMA) based on randomized sham-controlled trials in infants and children. The efficacy in adults with long disease history and advanced disease status is still widely unknown; the same applies to specific expectations of adult SMA patients and to what extent they are met and may impact outcome measures.!##!Methods!#!In a longitudinal monocentric study in adult patients with SMA types 2-4, the Stanford Expectations of Treatment Scale (SETS) was assessed prior to and during nusinersen treatment. Treatment outcome was evaluated using patient-reported outcomes (PROs) as well as objectively quantifiable motor outcome measures.!##!Results!#!Adult SMA patients had high expectations of nusinersen treatment effectiveness regarding increase in muscle strength and disease stabilization. Via PROs, 75% stated improvements in muscle strength, endurance and independence under therapy which was in line with slight improvements in quantifiable motor scores during a  ten month observation period. In contrast, patients only expressed few negative expectations which further decreased during therapy.!##!Conclusions!#!This study showed mainly positive treatment expectations and PROs in patients undergoing nusinersen treatment along with measurable functional improvement in adult SMA patients. Moreover, treatment expectations did not significantly influence outcome measures

Cerebrospinal Fluid Parameters in Antisense Oligonucleotide-Treated Adult 5q-Spinal Muscular Atrophy Patients

Approval of nusinersen, an intrathecally administered antisense oligonucleotide, for the treatment of 5q-spinal muscular atrophy (SMA) marked the beginning of a new therapeutic era in neurological diseases. Changes in routine cerebrospinal fluid (CSF) parameters under nusinersen have only recently been described in adult SMA patients. We aimed to explore these findings in a real-world setting and to identify clinical and procedure-associated features that might impact CSF parameters. Routinely collected CSF parameters (leukocyte count, lactate, total protein, CSF/serum albumin quotient (QAlbumin), oligoclonal bands) of 28 adult SMA patients were examined for up to 22 months of nusinersen treatment. Total protein and QAlbumin values significantly increased in the first 10 months, independent of the administration procedure. By month 14, no further increases were detected. Two patients developed transient pleocytosis. In two cases, positive oligoclonal bands were found in the beginning and in four patients throughout the whole observation period. No clinical signs of inflammatory central nervous system disease were apparent. Our data confirm elevated CSF total protein and QAlbumin during nusinersen treatment. These alterations may be caused by both repeated lumbar punctures and the interval between procedures rather than by the medication itself. Generally, there were no severe alterations of CSF routine parameters. These results further underline the safety of nusinersen therapy

Chemokine CXCL13 as a New Systemic Biomarker for B-Cell Involvement in Acute T Cell-Mediated Kidney Allograft Rejection

The presence of B-cell clusters in allogenic T cell-mediated rejection (TCMR) of kidney allografts is linked to more severe disease entities. In this study we characterized B-cell infiltrates in patients with TCMR and examined the role of serum CXCL-13 in these patients and experimentally. CXCL-13 serum levels were analyzed in 73 kidney allograft recipients at the time of allograft biopsy. In addition, four patients were evaluated for CXCL13 levels during the first week after transplantation. ELISA was done to measure CXCL-13 serum levels. For further mechanistic understanding, a translational allogenic kidney transplant (ktx) mouse model for TCMR was studied in BalbC recipients of fully mismatched transplants with C57BL/6 donor kidneys. CXCL-13 serum levels were measured longitudinally, CD20 and CD3 composition and CXCL13 mRNA in tissue were examined by flow cytometry and kidneys were examined by histology and immunohistochemistry. We found significantly higher serum levels of the B-cell chemoattractant CXCL13 in patients with TCMR compared to controls and patients with borderline TCMR. Moreover, in patients with acute rejection within the first week after ktx, a >5-fold CXCL13 increase was measured and correlated with B-cell infiltrates in the biopsies. In line with the clinical findings, TCMR in mice correlated with increased systemic serum-CXCL13 levels. Moreover, renal allografts had significantly higher CXCL13 mRNA expression than isogenic controls and showed interstitial CD20+ B-cell clusters and CD3+ cell infiltrates accumulating in the vicinity of renal vessels. CXCL13 blood levels correlate with B-cell involvement in TCMR and might help to identify patients at risk of a more severe clinical course of rejection

Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder leading to muscle weakness and respiratory failure. Arimoclomol, a heat-shock protein-70 (HSP70) co-inducer, is neuroprotective in animal models of amyotrophic lateral sclerosis, with multiple mechanisms of action, including clearance of protein aggregates, a pathological hallmark of sporadic and familial amyotrophic lateral sclerosis. We aimed to evaluate the safety and efficacy of arimoclomol in patients with amyotrophic lateral sclerosis. ORARIALS-01 was a multinational, randomised, double-blind, placebo-controlled, parallel-group trial done at 29 centres in 12 countries in Europe and North America. Patients were eligible if they were aged 18 years or older and met El Escorial criteria for clinically possible, probable, probable laboratory-supported, definite, or familial amyotrophic lateral sclerosis; had an ALS Functional Rating Scale-Revised score of 35 or more; and had slow vital capacity at 70% or more of the value predicted on the basis of the participant's age, height, and sex. Patients were randomly assigned (2:1) in blocks of 6, stratified by use of a stable dose of riluzole or no riluzole use, to receive oral arimoclomol citrate 1200 mg/day (400 mg three times per day) or placebo. The Randomisation sequence was computer generated centrally. Investigators, study personnel, and study participants were masked to treatment allocation. The primary outcome was the Combined Assessment of Function and Survival (CAFS) rank score over 76 weeks of treatment. The primary outcome and safety were analysed in the modified intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03491462, and is completed. Between July 31, 2018, and July 17, 2019, 287 patients were screened, 245 of whom were enrolled in the trial and randomly assigned. The modified intention-to-treat population comprised 239 patients (160 in the arimoclomol group and 79 in the placebo group): 151 (63%) were male and 88 (37%) were female; mean age was 57·6 years (SD 10·9). CAFS score over 76 weeks did not differ between groups (mean 0·51 [SD 0·29] in the arimoclomol group vs 0·49 [0·28] in the placebo group; p=0·62). Cliff's delta comparing the two groups was 0·039 (95% CI –0·116 to 0·194). Proportions of participants who died were similar between the treatment groups: 29 (18%) of 160 patients in the arimoclomol group and 18 (23%) of 79 patients in the placebo group. Most deaths were due to disease progression. The most common adverse events were gastrointestinal. Adverse events were more often deemed treatment-related in the arimoclomol group (104 [65%]) than in the placebo group (41 [52%]) and more often led to treatment discontinuation in the arimoclomol group (26 [16%]) than in the placebo group (four [5%]). Arimoclomol did not improve efficacy outcomes compared with placebo. Although available biomarker data are insufficient to preclude future strategies that target the HSP response, safety data suggest that a higher dose of arimoclomol would not have been tolerated. Orphazyme