ObjectiveTwo randomized trials for patients with diffuse systemic sclerosis (SSc) demonstrated an overall survival (OS) and event-free survival (EFS) advantage of autologous hematopoietic stem cell transplantation (AHSCT) using CD34+ selected peripheral blood stem cells (PBSCs) compared with monthly cyclophosphamide (CY). We asked if an unmodified PBSC graft followed by maintenance mycophenolate mofetil (MMF) after AHSCT, instead of a CD34+ selected graft, could provide comparable AHSCT outcomes.MethodsTwenty patients with high-risk SSc were enrolled in a prospective, single-arm trial with CY 200 mg/kg and horse antithymocyte globulin (ATG; CY200/ATG), followed by unmanipulated autologous PBSC, and then MMF maintenance starting at 2 months after AHSCT.ResultsPoint estimates of OS and EFS at 5 years after AHSCT were 85% (95% confidence interval [CI] 60.4%-94.9%) and 75% (95% CI 50%-88.7%), respectively. Median follow-up was 7.5 years (range 5.6-11.6) after transplant for living patients. Eight patients (40%) required intensive care unit treatment early after transplant. Early transplant-related mortality occurred in two patients (10%). Five patients developed relapse/progression of SSc after AHSCT. Four of nine patients with anti-RNA polymerase III antibodies had prior scleroderma renal crisis and the lowest quartile of estimated glomerular filtration rate (eGFR) on study entry; all four patients developed prolonged organ failure/death early after transplant.ConclusionWe observed favorable OS and EFS after AHSCT for patients with SSc, using CY200/ATG, unmanipulated PBSCs, and MMF posttransplant maintenance, which was comparable to trials with CD34+ graft selection. We identified a possible risk factor, pretransplant low eGFR, for adverse outcomes after AHSCT.

Food insecurity (FI), defined as the lack of continuous access to adequate food, affects 17–55

Gut dysbiosis is linked to mortality and the development of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HSCT), but the impact of cutaneous dysbiosis remains unexplored. We performed a pilot observational study and obtained retroauricular and forearm skin swabs from 12 adult patients prior to conditioning chemotherapy/radiation, and at 1-week, 1-month and 3-months after allogeneic HSCT, and performed shotgun metagenomic sequencing. The cutaneous microbiome among HSCT patients was enriched for gram-negative bacteria such as E coli and Pseudomonas, fungi, and viruses. Enrichment with bacteriophages and Polyomavirus sp, was observed among patients who died within 1-year, while we observed longitudinal stability of the cutaneous microbiome at the 3-month time point among those who survived beyond 1 year post-HSCT, although these may simply be a reflection of the overall medical status of the patients. There was no association with fungal abundance and any of the outcomes observed. The cutaneous microbiome may be a reservoir of pathobionts among allogeneic HSCT patients. Our findings suggest that cutaneous dysbiosis exists post-HSCT, but the ultimate implication of this to patient outcomes remains to be seen. Larger studies are required.

Single-agent high-dose melphalan (HDM, 200 mg/m2) has been the most commonly used conditioning regimen prior to autologous stem cell transplant, since its introduction in 1992. We used a more aggressive alkylator-based conditioning regimen in an attempt to overcome early relapse and combat drug resistance. We present a retrospective comparison and long-term follow-up of newly diagnosed patients with multiple myeloma (MM) treated with induction followed by either high-dose carmustine (BCNU) and HDM, or HDM alone, both followed by autologous stem cell transplant (ASCT). Between 1997 and 2002, 104 patients were treated with BCNU/HDM; from 2001 to 2008, 103 patients were treated with HDM alone. Median follow-up of survivors was 78 and 68 months for the BCNU/HDM and HDM groups, respectively. The median PFS was significantly increased with the BCNU/HDM regimen (40.4 vs 20.5 months, P<0.001). Median overall survival was increased with the BCNU/HDM regimen when compared with HDM alone (88.4 vs 67.2 months, P=0.07), but the difference was not statistically significant. Transplant-related mortality was similar in both groups (2.9% with BCNU and HDM vs 3.9% with HDM alone). Our findings suggest that the BCNU/HDM preparative regimen should be investigated further and potentially compared in a prospective randomized manner with HDM alone.

Preclinical models of inherited and induced autoimmune diseases (AIDs) have shown that hematopoietic stem cell transplantation (HSCT) following high-dose immunosuppressive conditioning could reverse organ damage and alter the course of AIDs. The rationale for both autologous and allogeneic HSCT has been based upon a reset of the immune system. Clinical application of HSCT was initially focused on severe systemic sclerosis (SSc) and three randomized trials comparing autologous HSCT with standard cyclophosphamide (CY) demonstrated significant improvement in SSc measured 12-54 months after transplant. Meta-analysis of the three trials showed the relative risk of all-cause mortality after HSCT was 0.5 compared to CY. More recently, clinical improvements in several AIDs have been reported with CY/fludarabine preparation followed by CD19 chimeric antigen receptor (CAR) T-cell infusion. With follow-up of 4-29 months, major disease responses and full B-cell reconstitution have been observed while side effects have been modest. Industry and academic centers are active in developing these and other cellular products for AID treatments including CAR-NK, off the shelf CAR-Ts, chimeric autoantibody receptor (CAAR-Ts), and mesenchymal stromal cells (MSCs). Clinical improvements after MSC administration have been reported, but as with the CAR-T trials, follow-up is still brief. Shared decision making with patients considering cellular therapy is perhaps easier for autologous HSCT since we have longer follow-up with many patients clinically improved and surviving off DMARDS for decades. Such individuals understandably view themselves as cured. Thus, the interest in the evolving role of cellular therapies in long-term improvement in severe AIDs.

ObjectiveIn the randomized Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial, myeloablation, followed by hematopoietic stem cell transplantation (HSCT), led to the normalization of systemic sclerosis (SSc) peripheral blood cell (PBC) gene expression signature at the 26‐month visit. Herein, we examined long‐term molecular changes ensuing 54 months after randomization for individuals receiving an HSCT or 12 months of intravenous cyclophosphamide (CYC).MethodsGlobal PBC transcript studies were performed in study participants at pretreatment baseline and at 38 months and 54 months after randomization, as well as in healthy controls using Illumina HT‐12 arrays.ResultsThirty (HSCT = 19 and CYC = 11) participants had 38‐month samples available, and 26 (HSCT = 16 and CYC = 11) had 54‐month samples available. In the paired comparison to baseline, a significant down‐regulation of interferon modules and an up‐regulation of cytotoxic/natural killer module were observed at the 38‐month and 54‐month visits in the HSCT arm, indicating a long‐term normalization of baseline SSc gene expression signature. No differentially expressed modules were detected in the CYC arm. In comparison to samples from healthy controls, 38‐month visit samples in the HSCT arm showed an up‐regulation of B cell and plasmablast modules and a down‐regulation of myeloid and inflammation modules. Importantly, 54‐month HSCT samples did not show any differentially expressed modules compared to healthy control samples, suggesting completion of immune reconstitution. Participants in the CYC arm continued to show an SSc transcript signature in comparison to controls at both time points.ConclusionParalleling the observed clinical benefit, HSCT leads to durable long‐term normalization of the molecular signature in SSc, with completion of immune resetting to 54 months after HSCT.image

PURPOSE: The COVID-19 global pandemic presented an insight into observing the changes in physical activity (PA) and sitting patterns of free-living adults during a unique period of intermittent enforced home confinement and free-living conditions. Evidence unequivocally indicates physical inactivity, facilitated by home confinement, is associated with greater risk of disease and mortality. This study aimed to monitor longitudinal PA and sitting patterns throughout the enforced COVID-19 restrictions, uniquely including all three UK national lockdowns between April 2020 and January 2021. METHODS: 580 adults (41 ± 21 y; 23% M / 77% F) participated in a longitudinal, observational study, encompassing all three UK national lockdowns between 19/4/20 - 23/1/21, using self-reported online surveys either daily or weekly for 6 months, then monthly to reduce survey fatigue. Pre-COVID data was based on the week prior to the first national lockdown. Participants recalled time engaging in PA and sitting per day for each diary completed throughout the study. Data was used to calculate MET-mins/week for total, low, moderate and vigorous activity, then averaged for each month. Friedman’s ranking test analysed differences between months for PA and sitting time. RESULTS: Total, low, moderate and vigorous MET-mins/wk were significantly different across months (p < 0.001) and tended to decline month-on-month (Table 1). PA levels were similar between lockdowns 2 and 3. Sitting time significantly increased (χ2(8) = 18, p = 0.02) across lockdowns 1-3, but decreased when restrictions were lifted. Table 1. Monthly mean (±SD) PA and sitting time patterns pre- and post-COVID, with L1-3 denoting each lockdown. - Post-COVID Months Pre-COVID 1 (L1) 2 3 4 5 6 7 (L2) 8 9 (L3) Total (MET-mins/wk) 2222 ± 2363 1233 ± 1612 1037 ± 1709 851 ± 1366 713 ± 1546 608 ± 1296 581 ± 1408 496 ± 1261 378 ± 1010 495 ± 1068 Low (MET-mins/wk) 699 ± 916 461 ± 760 409 ± 798 343 ± 646 266 ± 593 210 ± 442 177 ± 418 179 ± 436 168 ± 485 202 ± 441 Moderate (MET-mins/wk) 374 ± 807 252 ± 460 213 ± 473 165 ± 385 136 ± 467 110 ± 363 105 ± 587 95 ± 490 60 ± 294 57 ± 181 Vigorous (MET-mins/wk) 1149 ± 2124 520 ± 947 415 ± 868 343 ± 769 311 ± 864 288 ± 864 299 ± 994 222 ± 778 150 ± 515 236 ± 754 Sitting Time (mins/wk) 3184 ± 1462 3092 ± 1569 3203 ± 1440 3274 ± 1534 3515 ± 1694 3363 ± 1877 3183 ± 1493 3471 ± 1834 3437 ± 2073 3703 ± 1852 CONCLUSIONS: To avert the negative health impacts of ‘twindemics’ linking future disease pandemics and the physical inactivity pandemic, strict movement restrictions should be carefully considered in future given our data shows increased physical inactivity.

Objectives Myeloablative autologous haematopoietic stem cell transplant (HSCT) was recently demonstrated to provide significant benefit over cyclophosphamide (CYC) in the treatment of diffuse cutaneous systemic sclerosis (dcSSc) in the Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial. As dysregulation of the B cell compartment has previously been described in dcSSc, we sought to gain insight into the effects of myeloablative autologous HSCT as compared with CYC. Methods We sequenced the peripheral blood immunoglobulin heavy chain (IGH) repertoires in patients with dcSSc enrolled in the SCOT trial. Results Myeloablative autologous HSCT was associated with a sustained increase in IgM isotype antibodies bearing a low mutation rate. Clonal expression was reduced in IGH repertoires following myeloablative autologous HSCT. Additionally, we identified a underusage of immunoglobulin heavy chain V gene 5–51 in patients with dcSSc, and usage normalised following myeloablative autologous HSCT but not CYC treatment. Conclusions Together, these findings suggest that myeloablative autologous HSCT resets the IGH repertoire to a more naïve state characterised by IgM-expressing B cells, providing a possible mechanism for the elimination of pathogenic B cells that may contribute to the benefit of HSCT over CYC in the treatment of dcSSc.

Scleroderma is a rare, potentially fatal, clinically heterogeneous, systemic autoimmune connective tissue disorder that is characterized by progressive fibrosis of the skin and visceral organs, vasculopathy and immune dysregulation. The more severe form of the disease, diffuse cutaneous scleroderma (dcSSc), has no cure and limited treatment options. Haematopoietic stem cell transplantation has emerged as a potentially disease-modifying treatment but faces challenges such as toxicity associated with fully myeloablative conditioning and recurrence of autoimmunity. Novel cell therapies-such as mesenchymal stem cells, chimeric antigen receptor-based therapy, tolerogenic dendritic cells and facilitating cells-that may restore self-tolerance with more favourable safety and tolerability profiles are being explored for the treatment of dcSSc and other autoimmune diseases. This narrative review examines these evolving cell therapies.

Herpes zoster (HZ) and HZ-associated pain greatly affect patients quality of life, particularly in older andimmunocompromised adults, for whom comorbidities and polypharmacy are often reported. Three phase III,randomized, placebo-controlled clinical trials have reported the adjuvanted recombinant zoster vaccine (RZV) ashighly efficacious in preventing HZ and reducing pain severity in healthy adults 50 years old (Zoster Efficacy Study[ZOE]-50 study, NCT01165177) and 70 years old (ZOE-70; NCT01165229) and in immunocompromised adults18 years old undergoing autologous hematopoietic stem cell transplantation (ZOE-HSCT; NCT01610414). Here,we investigated efficacy of RZV in reducing (i) the duration of clinically significant pain (Zoster Brief Pain Inventorypain score 3) and (ii) HZ-associated pain medication use and duration of use in participants with confirmed HZ(breakthrough cases) from the 3 studies. Recombinant zoster vaccine effectively reduced the duration of clinicallysignificant HZ-associated pain during HZ episodes by 38.5% (P-value: 0.010) in the ZOE-HSCT study. Althougha similar trend was observed in the ZOE-50 and ZOE-70 studies, the results were not statistically significant becauseof the high vaccine efficacy (VE) against HZ resulting in rare breakthrough cases.VE in reducing pain medication use(39.6%;P-value: 0.008) and duration of medication use (49.3%, P-value: 0.040) was reported in the ZOE-70 study;corresponding positive VE estimates were observed in the ZOE-50 and ZOE-HSCT studies but were not statisticallysignificant. Data reported here demonstrate efficacy of RZV in reducing HZ-associated pain duration and painmedication use in breakthrough cases, thereby improving quality of life of those with HZ.

Objectives Results from the SCOT (Scleroderma: Cyclophosphamide Or Transplantation) clinical trial demonstrated significant benefits of haematopoietic stem cell transplant (HSCT) versus cyclophosphamide (CTX) in patients with systemic sclerosis. The objective of this study was to test the hypothesis that transplantation stabilises the autoantibody repertoire in patients with favourable clinical outcomes. Methods We used a bead-based array containing 221 protein antigens to profile serum IgG autoantibodies in participants of the SCOT trial. Results Comparison of autoantibody profiles at month 26 (n=23 HSCT; n=22 CTX) revealed antibodies against two viral antigens and six self-proteins (SSB/La, CX3CL1, glycyl-tRNA synthetase (EJ), parietal cell antigen, bactericidal permeability-increasing protein and epidermal growth factor receptor (EGFR)) that were significantly different between treatment groups. Linear mixed model analysis identified temporal increases in antibody levels for hepatitis B surface antigen, CCL3 and EGFR in HSCT-treated patients. Eight of 32 HSCT-treated participants and one of 31 CTX-treated participants had temporally varying serum antibody profiles for one or more of 14 antigens. Baseline autoantibody levels against 20 unique antigens, including 9 secreted proteins (interleukins, IL-18, IL-22, IL-23 and IL-27), interferon-α2A, stem cell factor, transforming growth factor-β, macrophage colony-stimulating factor and macrophage migration inhibitory factor were significantly higher in patients who survived event-free to month 54. Conclusions Our results suggest that HSCT favourably alters the autoantibody repertoire, which remains virtually unchanged in CTX-treated patients. Although antibodies recognising secreted proteins are generally thought to be pathogenic, our results suggest a subset could potentially modulate HSCT in scleroderma.

Compared with the general population, older adults with immune senescence and individuals who are immunocompromised (IC) due to disease or immunosuppressive therapy are at increased risk for herpes zoster (HZ) and its associated complications, which can be debilitating and life-threatening. Vaccination can be an effective strategy against HZ and studies have shown that HZ vaccination in IC individuals can elicit immune responses and provide protection from infection. Recently, the first approvals have been granted in the United States and the European Union for the recombinant HZ vaccine (RZV) in adults >= 18 years of age at risk of HZ due to immunodeficiency or immunosuppression. Existing systematic reviews have highlighted the risks for HZ in limited immunocompromising conditions and have only examined clinical data for RZV. This review details the risks and burden of HZ in a broad range of clinically relevant IC populations and summarizes key efficacy and safety data for RZV and live HZ vaccine in these individuals. Research has shown IC individuals can benefit from HZ vaccination; however, these insights have yet to be fully incorporated into vaccination guidelines and clinical care. Clinicians should consider HZ vaccination in eligible at-risk populations to protect against HZ and its associated complications and thereby, reduce the burden that HZ poses on the healthcare system. Electronic health records and linked personal health records could be used to identify and contact patients eligible for HZ vaccination and provide clinical decision support-generated alerts for missing or delayed vaccinations. This review will help clinicians identify eligible IC individuals who may benefit from HZ vaccination. A video abstract linked to this article is available on Figshare https://doi.org/10.6084/m9.figshare. 21517605. (c) 2022 GlaxoSmithKline Biologicals S.A. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

We previously conducted a single-arm feasibility study (STRIDE1) of myeloablative bone marrow transplantation (BMT) in adolescents and young adults with sickle cell disease (SCD). The trial identified donors before entry, enrolled well, and found no unexpected regimen-related toxicity. Although many single-arm studies have been published, there are no controlled trials of either BMT or gene therapy in SCD. Therefore, we designed a comparative trial by biological assignment (available donor versus no donor). This multicenter National Institutes of Health-funded study (Blood and Marrow Transplant Clinical Trials Network 1503; STRIDE2) enrolled patients between 2016 and 2021 at 35 sites. Lagging recruitment led to study closure, and here we report the impediments to accrual. The BMT regimen and entry criteria were from STRIDE1, and 2-year survival was the primary endpoint. To minimize selection bias from prior HLA typing, STRIDE2 excluded individuals with previously identified donors. Accrual was stopped at 69% of target (138 enrolled; assigned 28 with donor, 96 with no donor). Barriers to enrollment included lower than expected frequency of HLA-matched related and unrelated donors; loss of enrollees owing to previously identified donors; conventional care arm dissuading some seeking BMT; challenging short-term endpoints in SCD, including incomplete documentation of sickle pain episodes; state Medicaid (primary insurers of SCD) denial of BMT coverage for adult SCD despite the study having secured Coverage with Evidence Development from the Center for Medicare & Medicaid Services; slowed accrual in 2019 to 2021 during the Coronavirus disease 2019 pandemic; and restriction of BMT resourcing for nonmalignant diseases by academic medical (cancer) centers. Social obstacles and access to BMT centers also limited entry, as did practitioner and participant concerns over suitability, cost, and toxicity. Planning for future controlled trials of curative therapy in SCD and other nonmalignant diseases likely will meet these enrollment challenges. Lessons from this trial may aid the development of future comparative studies.

BackgroundIndividuals with autoimmune diseases (AIDs) are particularly vulnerable to herpes zoster (HZ) and its related complications. Although the live attenuated HZ vaccine is contraindicated in many of these individuals, the two-dose non-live recombinant zoster vaccine (RZV) can be used in immunosuppressed individuals. Based on accumulating data from RZV studies within specific immunosuppressive conditions, recently updated guidelines recommend RZV not only in immunocompetent adults aged ≥50 years, but also in adults aged ≥18 years (EU)/≥19 years (USA) at risk of HZ due to immunodeficiency or immunosuppression.1–3ObjectivesTo evaluate the burden of HZ in individuals with AIDs and the use of RZV as a preventative strategy.MethodsWe reviewed PubMed for available data on HZ incidence, summarised RZV data (effectiveness and safety) and the current recommendations for RZV in individuals with AIDs. The latest search was conducted in September 2021.ResultsHZ incidence in the general population is 4–7/1000 person-years (increases with age) and 8–15/1000 person-years in individuals with AIDs. Common immunosuppressive and immunomodulatory therapies can predispose individuals to HZ, as shown by large meta-analyses of interventional and observational studies. No published randomised controlled trial data of RZV in AID populations were found in our search. In two retrospective cohort studies in patients with inflammatory bowel disease (IBD), 4,5 RZV demonstrated high vaccine effectiveness (OR 0.64; 95% CI 0.44, 0.77).4 In a real-world observational study investigating RZV in beneficiaries of the Medicare national health insurance program in the USA, individuals with AIDs achieved vaccine effectiveness of 68.0% (95% CI 62.3%, 72.8%), which was similar to the overall population (70.1% [95% CI 68.6%, 71.5%]).6 In two single-centre, retrospective studies of RZV in individuals with AIDs, including rheumatoid arthritis (RA), adverse events after the first RZV dose were mild7,8. Disease flares were uncommon, mild and self-limiting, although a flare at the first RZV dose was significantly associated with an increased risk of a flare at the second dose (hazard ratio 3.9; P=0.0015)7. In addition, glucocorticoid use during vaccination was significantly associated with flares (odds ratio [OR] 2.31; P=0.004; Lenfant, 2021)7. In a study of individuals with IBD, receiving ≥1 RZV dose was associated with a low flare rate9. Current RZV guidelines vary by country and will be revised as new data emerge. Ongoing studies include phase 4 studies of individuals with RA and IBD receiving immunotherapies, and a study investigating the immunogenicity and safety of RZV in individuals with stable systemic lupus erythematosus.ConclusionIndividuals with AIDs are at increased risk of HZ and its related complications, which may be due to either or both of their underlying condition and the treatment(s) they are receiving. The developing collective scientific evidence from the published literature on RZV in individuals with AIDs demonstrates a favourable benefit:risk profile for RZV in this population which contributed to the recent USA ACIP recommendation. Further studies are warranted to evaluate potential effects of individual conditions and immunotherapies on vaccine efficacy and methods to optimise vaccine use.References[1]Dooling KL, et al. MMWR Morb Mortal Wkly Rep, 2018[2]GlaxoSmithKline, Press Release, 2021[3]GlaxoSmithKline, RZV EU SmPC, 2021[4]Kochhar GS, et al. Vaccine, 2021[5]Khan N, et al. Clin Gastroenterol Hepatol, 2021[6]Izurieta HS, et al. Clin Infect Dis, 2021[7]Lenfant T, et al. Rheumatology, 2021[8]Stevens E, et al. ACR Open Rheumatol, 2020[9]Satyam VR, et al. Dig Dis Sci, 2020AcknowledgementsThis abstract was funded by GlaxoSmithKline Biologicals SA. Medical writing support in the preparation of this abstract was provided by Silvia Pregnolato of OPEN Health Communications, London, UK, with financial support from GlaxoSmithKline Biologicals SA.Disclosure of InterestsKevin Winthrop Consultant of: KLW has received consultancy fees from GlaxoSmithKline, Bristol Myers Squibb, Pfizer, AbbVie, Union Chimique Belge, Eli Lilly, Galapagos, Roche, Gilead, Sanofi, Regeneron, AstraZeneca and Novartis., Grant/research support from: KLW has received research grants from Bristol Myers Squibb and Pfizer., Francis A Farraye Consultant of: KMS has received consultancy fees from and been part of publication committees for GlaxoSmithKline., Keith M Sullivan Shareholder of: FAF is a stockholder in Innovation Pharmaceuticals., Paid instructor for: FAF sits on the data safety monitoring board for Eli Lilly and Theravance., Consultant of: FAF has received consultancy fees from Arena, Bristol Myers Squibb, Braintree Labs, GI reviewers, GlaxoSmithKline, Iterative Scopes, Janssen, Pfizer and Sebela., David O Willer Shareholder of: DOW holds restricted share stock ownership for GlaxoSmithKline., Employee of: DOW is employed by GlaxoSmithKline., Peter Vink Employee of: PV was an employee at GSK at the time this work was completed., Fernanda Tavares-Da-Silva Shareholder of: FTDS holds restricted share stock ownership for GlaxoSmithKline., Employee of: FTDS is employed by GlaxoSmithKline.