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  • 1
    Online Resource
    Online Resource
    Machine learning predicts stem cell transplant response in severe scleroderma
    BMJ ; 2020
    In:  Annals of the Rheumatic Diseases Vol. 79, No. 12 ( 2020-12), p. 1608-1615
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 79, No. 12 ( 2020-12), p. 1608-1615
    Abstract: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) trial demonstrated clinical benefit of haematopoietic stem cell transplant (HSCT) compared with cyclophosphamide (CYC). We mapped PBC (peripheral blood cell) samples from the SCOT clinical trial to scleroderma intrinsic subsets and tested the hypothesis that they predict long-term response to HSCT. Methods We analysed gene expression from PBCs of SCOT participants to identify differential treatment response. PBC gene expression data were generated from 63 SCOT participants at baseline and follow-up timepoints. Participants who completed treatment protocol were stratified by intrinsic gene expression subsets at baseline, evaluated for event-free survival (EFS) and analysed for differentially expressed genes (DEGs). Results Participants from the fibroproliferative subset on HSCT experienced significant improvement in EFS compared with fibroproliferative participants on CYC (p=0.0091). In contrast, EFS did not significantly differ between CYC and HSCT arms for the participants from the normal-like subset (p=0.77) or the inflammatory subset (p=0.1). At each timepoint, we observed considerably more DEGs in HSCT arm compared with CYC arm with HSCT arm showing significant changes in immune response pathways. Conclusions Participants from the fibroproliferative subset showed the most significant long-term benefit from HSCT compared with CYC. This study suggests that intrinsic subset stratification of patients may be used to identify patients with SSc who receive significant benefit from HSCT.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2020-217033
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2020
    detail.hit.zdb_id: 1481557-6
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  • 2
    Online Resource
    Online Resource
    Characterising the autoantibody repertoire in systemic sclerosis following myeloablative haematopoietic stem cell transplantation
    BMJ ; 2023
    In:  Annals of the Rheumatic Diseases Vol. 82, No. 5 ( 2023-05), p. 670-680
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 82, No. 5 ( 2023-05), p. 670-680
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/ard-2021-221926
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1481557-6
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  • 3
    Online Resource
    Online Resource
    Myeloablation followed by autologous stem cell transplantation normalises systemic sclerosis molecular signatures
    BMJ ; 2019
    In:  Annals of the Rheumatic Diseases Vol. 78, No. 10 ( 2019-10), p. 1371-1378
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 78, No. 10 ( 2019-10), p. 1371-1378
    Abstract: In the randomised scleroderma: Cyclophosphamide Or Transplantation (SCOT trial) ( NCT00114530 ), myeloablation, followed by haematopoietic stem cell transplantation (HSCT), led to improved clinical outcomes compared with monthly cyclophosphamide (CYC) treatment in systemic sclerosis (SSc). Herein, the study aimed to determine global molecular changes at the whole blood transcript and serum protein levels ensuing from HSCT in comparison to intravenous monthly CYC in 62 participants enrolled in the SCOT study. Methods Global transcript studies were performed at pretreatment baseline, 8 months and 26 months postrandomisation using Illumina HT-12 arrays. Levels of 102 proteins were measured in the concomitantly collected serum samples. Results At the baseline visit, interferon (IFN) and neutrophil transcript modules were upregulated and the cytotoxic/NK module was downregulated in SSc compared with unaffected controls. A paired comparison of the 26 months to the baseline samples revealed a significant decrease of the IFN and neutrophil modules and an increase in the cytotoxic/NK module in the HSCT arm while there was no significant change in the CYC control arm. Also, a composite score of correlating serum proteins with IFN and neutrophil transcript modules, as well as a multilevel analysis showed significant changes in SSc molecular signatures after HSCT while similar changes were not observed in the CYC arm. Lastly, a decline in the IFN and neutrophil modules was associated with an improvement in pulmonary forced vital capacity and an increase in the cytotoxic/NK module correlated with improvement in skin score. Conclusion HSCT contrary to conventional treatment leads to a significant ‘correction’ in disease-related molecular signatures.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/annrheumdis-2019-215770
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2019
    detail.hit.zdb_id: 1481557-6
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  • 4
    Online Resource
    Online Resource
    How well do coverage surveys and programmatically reported mass drug administration coverage match? Results from 214 mass drug administration campaigns in 15 countries, 2008–2017
    BMJ ; 2023
    In:  BMJ Global Health Vol. 8, No. 5 ( 2023-05), p. e011193-
    Details
    In: BMJ Global Health, BMJ, Vol. 8, No. 5 ( 2023-05), p. e011193-
    Abstract: Delivering preventive chemotherapy through mass drug administration (MDA) is a central approach in controlling or eliminating several neglected tropical diseases (NTDs). Treatment coverage, a primary indicator of MDA performance, can be measured through routinely reported programmatic data or population-based coverage evaluation surveys. Reported coverage is often the easiest and least expensive way to estimate coverage; however, it is prone to inaccuracies due to errors in data compilation and imprecise denominators, and in some cases measures treatments offered as opposed to treatments swallowed. Objective Analyses presented here aimed to understand (1) how often coverage calculated using routinely reported data and survey data would lead programme managers to make the same programmatic decisions; (2) the magnitude and direction of the difference between these two estimates, and (3) whether there is meaningful variation by region, age group or country. Methods We analysed and compared reported and surveyed treatment coverage data from 214 MDAs implemented between 2008 and 2017 in 15 countries in Africa, Asia and the Caribbean. Routinely reported treatment coverage was compiled using data reported by national NTD programmes to donors, either directly or via NTD implementing partners, following the implementation of a district-level MDA campaign; coverage was calculated by dividing the number of individuals treated by a population value, which is typically based on national census projections and occasionally community registers. Surveyed treatment coverage came from post-MDA community-based coverage evaluation surveys, which were conducted as per standardised WHO recommended methodology. Results Coverage estimates using routine reporting and surveys gave the same result in terms of whether the minimum coverage threshold was reached in 72% of the MDAs surveyed in the Africa region and in 52% in the Asia region. The reported coverage value was within ±10 percentage points of the surveyed coverage value in 58/124 of the surveyed MDAs in the Africa region and 19/77 in the Asia region. Concordance between routinely reported and surveyed coverage estimates was 64% for the total population and 72% for school-age children. The study data showed variation across countries in the number of surveys conducted as well as the frequency with which there was concordance between the two coverage estimates. Conclusions Programme managers must grapple with making decisions based on imperfect information, balancing needs for accuracy with cost and available capacity. The study shows that for many of the MDAs surveyed, based on the concordance with respect to reaching the minimum coverage thresholds, the routinely reported data were accurate enough to make programmatic decisions. Where coverage surveys do show a need to improve accuracy of routinely reported results, NTD programme managers should use various tools and approaches to strengthen data quality in order to use data for decision-making to achieve NTD control and elimination goals.
    Type of Medium: Online Resource
    ISSN: 2059-7908
    URL: Article
    DOI: 10.1136/bmjgh-2022-011193
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 2851843-3
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  • 5
    Online Resource
    Online Resource
    Myeloablative autologous haematopoietic stem cell transplantation resets the B cell repertoire to a more naïve state in patients with systemic sclerosis
    BMJ ; 2023
    In:  Annals of the Rheumatic Diseases Vol. 82, No. 3 ( 2023-03), p. 357-364
    Details
    In: Annals of the Rheumatic Diseases, BMJ, Vol. 82, No. 3 ( 2023-03), p. 357-364
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0003-4967 , 1468-2060
    URL: Article
    DOI: 10.1136/ard-2021-221925
    RVK:
    XA 10000
    Language: English
    Publisher: BMJ
    Publication Date: 2023
    detail.hit.zdb_id: 1481557-6
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  • 6
    Online Resource
    Online Resource
    Cohort profile: pathways to care among people with disorders of sex development (DSD)
    BMJ ; 2022
    In:  BMJ Open Vol. 12, No. 9 ( 2022-09), p. e063409-
    Details
    In: BMJ Open, BMJ, Vol. 12, No. 9 ( 2022-09), p. e063409-
    Abstract: The ‘DSD Pathways’ study was initiated to assess health status and patterns of care among people enrolled in large integrated healthcare systems and diagnosed with conditions comprising the broad category of disorders (differences) of sex development (DSD). The objectives of this communication are to describe methods of cohort ascertainment for two specific DSD conditions—classic congenital adrenal hyperplasia with 46,XX karyotype (46,XX CAH) and complete androgen insensitivity syndrome (CAIS). Participants Using electronic health records we developed an algorithm that combined diagnostic codes, clinical notes, laboratory data and pharmacy records to assign each cohort candidate a ‘strength-of-evidence’ score supporting the diagnosis of interest. A sample of cohort candidates underwent a review of the full medical record to determine the score cutoffs for final cohort validation. Findings to date Among 5404 classic 46,XX CAH cohort candidates the strength-of-evidence scores ranged between 0 and 10. Based on sample validation, the eligibility cut-off for full review was set at the strength-of-evidence score of ≥7 among children under the age of 8 years and ≥8 among older cohort candidates. The final validation of all cohort candidates who met the cut-off criteria identified 115 persons with classic 46,XX CAH. The strength-of-evidence scores among 648 CAIS cohort candidates ranged from 2 to 10. There were no confirmed CAIS cases among cohort candidates with scores 〈 6. The in-depth medical record review for candidates with scores ≥6 identified 61 confirmed cases of CAIS. Future plans As the first cohort of this type, the DSD Pathways study is well-positioned to fill existing knowledge gaps related to management and outcomes in this heterogeneous population. Analyses will examine diagnostic and referral patterns, adherence to care recommendations and physical and mental health morbidities examined through comparisons of DSD and reference populations and analyses of health status across DSD categories.
    Type of Medium: Online Resource
    ISSN: 2044-6055 , 2044-6055
    URL: Article
    URL: Article
    DOI: 10.1136/bmjopen-2022-063409
    DOI: 10.1136/bmjopen-2022-063409.supp1
    Language: English
    Publisher: BMJ
    Publication Date: 2022
    detail.hit.zdb_id: 2599832-8
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