Immune reconstitution after autologous hematopoietic stem cell transplantation in Crohn's disease: current status and future directions. A review on behalf of the EBMT Autoimmune Diseases Working Party and the autologous stem cell transplantation in refractory CD—low intensity therapy evaluation study investigators

Patients with treatment refractory Crohn’s disease (CD) suffer debilitating symptoms, poor quality of life, and reduced work productivity. Surgery to resect inflamed and fibrotic intestine may mandate creation of a stoma and is often declined by patients. Such patients continue to be exposed to medical therapy that is ineffective, often expensive and still associated with a burden of adverse effects. Over the last two decades, autologous hematopoietic stem cell transplantation (auto-HSCT) has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies have provided proof of concept that auto-HSCT can restore immunological tolerance in chronic autoimmunity via the eradication of pathological immune responses and a profound reconfiguration of the immune system. Herein, we review current experience of auto-HSCT for the treatment of CD as well as approaches that have been used to monitor immune reconstitution following auto-HSCT in patients with ADs, including CD. We also detail immune reconstitution studies that have been integrated into the randomized controlled Autologous Stem cell Transplantation In refractory CD—Low Intensity Therapy Evaluation trial, which is designed to test the hypothesis that auto-HSCT using reduced intensity mobilization and conditioning regimens will be a safe and effective means of inducing sustained control in refractory CD compared to standard of care. Immunological profiling will generate insight into the pathogenesis of the disease, restoration of responsiveness to anti-TNF therapy in patients with recurrence of endoscopic disease and immunological events that precede the onset of disease in patients that relapse after auto-HSCT

Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party

Three randomized controlled trials in early severe systemic sclerosis demonstrated that autologous hematopoietic stem cell transplantation was superior to standard cyclophosphamide therapy. This European Society for Blood and Marrow Transplantation multicenter, prospective, non-interventional study was designed to further decipher efficacy and safety of this procedure for severe systemic sclerosis patients in real-life practice and to search for prognostic factors. All consecutive adult patients with systemic sclerosis undergoing a first autologous hematopoietic stem cell transplant between December 2012 and February 2016 were prospectively included in the study. The primary endpoint was progression-free survival. Secondary endpoints were overall survival, non-relapse mortality, response and incidence of progression. Eighty patients with systemic sclerosis were included. The median duration of the follow-up was 24 (range, 6-57) months after stem cell transplantation using cyclophosphamide plus antithymocyte globulin conditioning for all, with CD34(+) selection in 35 patients. At 2 years, the progression-free survival rate was 81.8%, the overall survival rate was 90%, the response rate was 88.7% and the incidence of progression was 11.9%. The 100-day non-relapse mortality rate was 6.25% (n=5) with four deaths from cardiac events, including three due to cyclophosphamide toxicity. Modified Rodnan skin score and forced vital capacity improved with time (P24 and older age at transplantation were associated with lower progression-free survival (hazard ratios 3.32 and 1.77, respectively). CD34(+)-cell selection was associated with better response (hazard ratio 0.46). This study confirms the efficacy of autologous stem cell transplantation, using non-myeloablative conditioning, in real-life practice for severe systemic sclerosis. Careful cardio-pulmonary assessment to identify organ involvement at the time of the patient's referral, reduced cyclophosphamide doses and CD34(+)-cell selection may improve outcomes.Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Safety and efficacy of autologous haematopoietic stem-cell transplantation with low-dose cyclophosphamide mobilisation and reduced intensity conditioning versus standard of care in refractory Crohn’s disease (ASTIClite): an open-label, multicentre, randomised controlled trial

Background A previous controlled trial of autologous haematopoietic stem-cell transplantation (HSCT) in patients with refractory Crohn's disease did not meet its primary endpoint and reported high toxicity. We aimed to assess the safety and efficacy of HSCT with an immune-ablative regimen of reduced intensity versus standard of care in this patient population. Methods This open-label, multicentre, randomised controlled trial was conducted in nine National Health Service hospital trusts across the UK. Adults (aged 18–60 years) with active Crohn's disease on endoscopy (Simplified Endoscopic Score for Crohn's Disease [SES-CD] ulcer sub-score of ≥2) refractory to two or more classes of biological therapy, with no perianal or intra-abdominal sepsis or clinically significant comorbidity, were recruited. Participants were centrally randomly assigned (2:1) to either HSCT with a reduced dose of cyclophosphamide (intervention group) or standard care (control group). Randomisation was stratified by trial site by use of random permuted blocks of size 3 and 6. Patients in the intervention group underwent stem-cell mobilisation (cyclophosphamide 1 g/m2 with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg) and stem-cell harvest (minimum 2·0 × 106 CD34+ cells per kg), before conditioning (fludarabine 125 mg/m2, cyclophosphamide 120 mg/kg, and rabbit anti-thymocyte globulin [thymoglobulin] 7·5 mg/kg in total) and subsequent stem-cell reinfusion supported by G-CSF. Patients in the control group continued any available conventional, biological, or nutritional therapy. The primary outcome was absence of endoscopic ulceration (SES-CD ulcer sub-score of 0) without surgery or death at week 48, analysed in the intention-to-treat population by central reading. This trial is registered with the ISRCTN registry, 17160440. Findings Between Oct 18, 2018, and Nov 8, 2019, 49 patients were screened for eligibility, of whom 23 (47%) were randomly assigned: 13 (57%) to the intervention group and ten (43%) to the control group. In the intervention group, ten (77%) participants underwent HSCT and nine (69%) reached 48-week follow-up; in the control group, nine (90%) reached 48-week follow-up. The trial was halted in response to nine reported suspected unexpected serious adverse reactions in six (46%) patients in the intervention group, including renal failure due to proven thrombotic microangiopathy in three participants and one death due to pulmonary veno-occlusive disease. At week 48, absence of endoscopic ulceration without surgery or death was reported in three (43%) of seven participants in the intervention group and in none of six participants in the control group with available data. Serious adverse events were more frequent in the intervention group (38 in 13 [100%] patients) than in the control group (16 in four [40%] patients). A second patient in the intervention group died after week 48 of respiratory and renal failure. Interpretation Although HSCT with an immune-ablative regimen of reduced intensity decreased endoscopic disease activity, significant adverse events deem this regimen unsuitable for future clinical use in patients with refractory Crohn's disease. Funding Efficacy and Mechanism Evaluation Programme, a Medical Research Council and National Institute for Health Research partnership

Assessment of Cognitive Status in Geriatric Neurology

The elements of a comprehensive mental status examination include observational, cognitive, and neuropsychiatric assessments. Although each of these elements is presented separately in this chapter, they are inter‐related and collectively characterize the neurobehavioral function of the patient. As the frequency of cognitive disorders increases dramatically with advancing age, examination of mental status is one of the most important components of the neurologic examination. The chapter shows examples of general cognitive tests such as mini‐mental state examination (MMSE) test and mini cognitive assessment instrument (Mini‐Cog), that are practical to use in geriatric patients in clinical setting. Whether the clinician designs his/her own unique assessments or utilizes one of the many standardized instruments available, failure to include a mental status examination in the assessment of older adults represents a missed opportunity