Publications | Nathan Constantine-Cooke

Publications

Recent publications I have contributed to.

2022

  1. medRxiv
    Longitudinal Faecal Calprotectin Profiles Characterise Disease Course Heterogeneity in Crohn’s Disease
    Nathan Samuel Constantine-Cooke, Karla Monterrubio Gomez, Nikolas Plevris, Lauranne A.A.P Derikx, Beatriz Gros, Gareth-Rhys Jones, Riccardo MarioniCharlie W. Lees, and Catalina Vallejos
    Oct 2022

    Background and Aims: The progressive nature of Crohn’s disease is highly variable and hard to predict. In addition, symptoms correlate poorly with mucosal inflammation. There is therefore an urgent need to better characterise the heterogeneity of disease trajectories in Crohn’s disease by utilising objective markers of inflammation. We aimed to better understand this heterogeneity by clustering Crohn’s disease patients with similar longitudinal faecal calprotectin profiles. Methods Latent class mixed models were used to model faecal calprotectin trajectories within five years of diagnosis and to cluster subjects. Information criteria, alluvial plots, and cluster trajectories were used to decide the optimal number of clusters. Chi-squared, Fisher’s exact test, and ANOVA were used to test for associations with variables commonly assessed at diagnosis. Results: Our study cohort comprised of 365 patients with newly diagnosed Crohn’s disease and 2856 faecal calprotectin measurements taken within five years of diagnosis (median 7 per subject). Four distinct clusters were identified by characteristic calprotectin profiles: a cluster with consistently high faecal calprotectin and three clusters characterised by different downward longitudinal trends. Cluster membership was significantly associated with smoking (p = 0.015), upper gastrointestinal involvement (p < 0.001), and early biologic therapy (p < 0.001). Conclusions: Our analysis demonstrates a novel approach to characterising the heterogeneity of Crohn’s disease by using faecal calprotectin. The group profiles do not simply reflect different treatment regimes and do not mirror classical disease progression endpoints. We believe these profiles represent an entirely new way of classifying disease behaviour in Crohn’s disease.

    @article{ConstantineCooke2022,
      abbr = {medRxiv},
      bibtex_show = {true},
      pdf = lcmm-preprint.pdf,
      selected = {true},
      author = {Constantine-Cooke, Nathan Samuel and Gomez, Karla Monterrubio and Plevris, Nikolas and Derikx, Lauranne A.A.P and Gros, Beatriz and Jones, Gareth-Rhys and Marioni, Riccardo and Lees, Charlie W. and Vallejos, Catalina},
      title = {Longitudinal Faecal Calprotectin Profiles Characterise Disease Course Heterogeneity in Crohn's Disease},
      year = {2022},
      month = oct,
      doi = {10.1101/2022.08.16.22278320},
      publisher = {Cold Spring Harbor Laboratory},
      url = {https://doi.org/10.1101/2022.08.16.22278320}
    }
  2. DLD
    Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn’s disease
    Lauranne A.A.P. Derikx, Nikolas Plevris, Shanna Su, Beatriz Gros, Mathew Lyons, Spyros I. Siakavellas,  Nathan Constantine-Cooke, Philip Jenkinson, Claire O’Hare, Colin Noble, Ian D. Arnott, Gareth-Rhys Jones, and Charlie W Lees
    Digestive and Liver Disease Oct 2022

    Background:The UNITI trial reports efficacy of ustekinumab (UST) dose intensification in Crohn’s disease (CD) from 12- to 8-weekly, but not 4-weekly. We aimed 1) to assess the cumulative incidence of UST dose intensification to 4- or 6-weekly, 2) to identify factors associated with dose intensification, and 3) to assess the effectiveness of this strategy. Methods: We performed a retrospective, observational cohort study in NHS Lothian including all UST treated CD patients (2015-2020). Results: 163 CD patients were treated with UST (median follow-up: 20.3 months [13.4-38.4]), of whom 55 (33.7%) underwent dose intensification to 4-weekly (n = 50, 30.7%) or 6-weekly (n = 5, 3.1%). After 1 year 29.9% were dose intensified. Prior exposure to both anti-TNF and vedolizumab (HR 9.5; 1.3-70.9), and concomitant steroid use at UST start (HR 1.8; 1.0-3.1) were associated with dose intensification. Following dose intensification, 62.6% patients (29/55) remained on UST beyond 1 year. Corticosteroid-free clinical remission was achieved in 27% at week 16 and 29.6% at last follow-up. Conclusion: One third of CD patients treated with UST underwent dose intensification to a 4- or 6-weekly interval within the first year. Patients who failed both anti-TNF and vedolizumab, or required steroids at initiation were more likely to dose intensify.

    @article{DERIKX2022,
      abbr = {DLD},
      bibtex_show = {true},
      title = {Rates, predictive factors and effectiveness of ustekinumab intensification to 4- or 6-weekly intervals in Crohn's disease},
      journal = {Digestive and Liver Disease},
      month = oct,
      year = {2022},
      issn = {1590-8658},
      doi = {https://doi.org/10.1016/j.dld.2022.10.002},
      url = {https://www.sciencedirect.com/science/article/pii/S1590865822007344},
      author = {Derikx, Lauranne A.A.P. and Plevris, Nikolas and Su, Shanna and Gros, Beatriz and Lyons, Mathew and Siakavellas, Spyros I. and Constantine-Cooke, Nathan and Jenkinson, Philip and O'Hare, Claire and Noble, Colin and Arnott, Ian D. and Jones, Gareth-Rhys and Lees, Charlie W},
      keywords = {Crohn's disease, Dose escalation, Dose optimisation, Real world evidence, Ustekinumab}
    }
  3. AP&T
    Patterns of emergency admission for IBD patients over the last 10 years in Lothian, Scotland: A retrospective prevalent cohort analysis
    Mathew Lyons, Lauranne A. A. P. Derikx, James Fulforth, Sophie McCall, Nikolas Plevris, Philip W. Jenkinson, Kathryn Kirkwood, Spyros Siakavellas, Laura Lucaciu,  Nathan Constantine-Cooke, Ian D. Arnott, Paul Henderson, Richard K. Russell, David C. Wilson, Charlie W. Lees, and Gareth-Rhys Jones
    Alimentary Pharmacology & Therapeutics Mar 2022

    Objective: It is unclear how the compounding prevalence of inflammatory bowel disease (IBD) has translated into the causes and rates of hospitalisation, particularly in an era of increased biologic prescribing. We aimed to analyse these trends in a population-based IBD cohort over the last 10 years. Design: The Lothian IBD registry is a complete, validated, prevalent database of IBD patients in NHS Lothian, Scotland. ICD-10 coding of hospital discharge letters from all IBD patient admissions to secondary care between 1 January 2010 and 31 December 2019 was interrogated for admission cause, with linkage to local/national data sets on death and prescribed drugs. Results: Fifty-seven per cent (4673/8211) of all IBD patients were admitted to secondary care for >24 h between 1 January 2010 and 31 December 2019. In patients <40 years, IBD was the commonest reason for admission (38% of admissions), whereas infection was the most common cause in those >60 years (19% of admissions). Three per cent (243/8211) of IBD patients accounted for 50% of the total IBD bed-days over the study period. Age-standardised IBD admission rates fell from 39.4 to 25.5 admissions per 100,000 population between 2010 and 2019, an average annual percentage reduction of 3% (95% CI -4.5% to -2.1%, p < 0.0001). Non-IBD admission rates were unchanged overall (145-137 per 100,000 population) and specifically for serious (hospitalisation) and severe (ITU admission or death) infection over the same period. Conclusion: Despite compounding prevalence and increased biologic use, IBD admission rates are falling. The cause of admission varies with age, with infection the predominant cause in older patients.

    @article{Lyons2022,
      abbr = {AP&T},
      bibtex_show = {true},
      title = {Patterns of emergency admission for IBD patients over the last 10 years in Lothian, Scotland: A retrospective prevalent cohort analysis},
      author = {Lyons, Mathew and Derikx, Lauranne A. A. P. and Fulforth, James and McCall, Sophie and Plevris, Nikolas and Jenkinson, Philip W. and Kirkwood, Kathryn and Siakavellas, Spyros and Lucaciu, Laura and Constantine-Cooke, Nathan and Arnott, Ian D. and Henderson, Paul and Russell, Richard K. and Wilson, David C. and Lees, Charlie W. and Jones, Gareth-Rhys},
      year = {2022},
      month = mar,
      language = {English},
      journal = {Alimentary Pharmacology \& Therapeutics},
      publisher = {Elsevier},
      keywords = {epidemiology, infection, inflammatory bowel disease},
      doi = {https://doi.org/10.1111/apt.16867},
      url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/apt.16867},
      eprint = {https://onlinelibrary.wiley.com/doi/pdf/10.1111/apt.16867}
    }

2021

  1. TAG
    Real-world experience with tofacitinib in ulcerative colitis: a systematic review and meta-analysis
    Laura A. Lucaciu,  Nathan Constantine-Cooke, Nikolas Plevris, Spyros Siakavellas, Lauranne A.A.P. Derikx, Gareth-Rhys Jones, and Charles W. Lees
    Therapeutic Advances in Gastroenterology Dec 2021

    Background and aims: Tofacitinib is a Janus kinase inhibitor (JAKi) recently approved for the treatment of moderate to severe ulcerative colitis (UC) based on robust efficacy and safety data derived from OCTAVE clinical trials. Evidence on the outcomes of tofacitinib therapy in real-world UC patients is needed, as a number of these patients would be deemed ineligible for clinical trials. We have therefore summarised data derived from observational, real-world evidence (RWE) studies on the effectiveness and safety of tofacitinib in moderate to severe UC patients. Methods: We searched the PubMed, EMBASE, Scopus, Web of Science and Cochrane databases for observational studies on the use of tofacitinib in UC patients, published between 30 May 2018 and 24 January 2021. Pooled induction (8-14 weeks) and maintenance (16-26 weeks) clinical response and remission rates were calculated, as well as the proportion of reported adverse events using random effects models. Results: Nine studies were included, comprising 830 patients, of which 81% were previously treated with anti-tumour necrosis factor (TNF) and 57% with vedolizumab. Induction of clinical response and remission were achieved in 51% (95% confidence interval, 41-60%) and 37% (26-45%) of patients, after a median follow-up of 8 weeks. At the end of a median follow-up of 24 weeks, maintenance of clinical response and remission were met in 40% (31-50%) and 29% (23-36%) of patients, respectively. Thirty-two percent of the patients had at least one adverse event, the most commonly reported being mild infection (13%) and worsening of UC, requiring colectomy (13%). A third of the patients (35%) discontinued tofacitinib, most frequently due to primary non-response (51%). Conclusion: Tofacitinib is a safe and effective therapy in real-world UC patients, as previously reported by clinical trials.

    @article{doi:10.1177/17562848211064004,
      abbr = {TAG},
      bibtex_show = {true},
      selected = {true},
      pdf = tag2021.pdf,
      author = {Lucaciu, Laura A. and Constantine-Cooke, Nathan and Plevris, Nikolas and Siakavellas, Spyros and Derikx, Lauranne A.A.P. and Jones, Gareth-Rhys and Lees, Charles W.},
      title = {Real-world experience with tofacitinib in ulcerative colitis: a systematic review and meta-analysis},
      journal = {Therapeutic Advances in Gastroenterology},
      volume = {14},
      number = {},
      pages = {17562848211064004},
      month = dec,
      year = {2021},
      doi = {10.1177/17562848211064004},
      note = {PMID: 34987608},
      url = {https://doi.org/10.1177/17562848211064004},
      eprint = {https://doi.org/10.1177/17562848211064004}
    }
  2. JCC
    Effectiveness and safety of adalimumab biosimilar SB5 in IBD: outcomes in originator to SB5 switch, double biosimilar switch and bio-naieve SB5 observational cohorts
    Lauranne A A P Derikx, Heather W Dolby, Nikolas Plevris, Laura Lucaciu, Caitlin S Rees, Mathew Lyons, Spyros I Siakavellas,  Nathan Constantine-Cooke, Philip Jenkinson, Shanna Su, Claire O’Hare, Laura Kirckpatrick, Lynne M Merchant, Colin Noble, Ian D Arnott, Gareth-Rhys Jones, and Charlie W Lees
    Journal of Crohn’s and Colitis Jun 2021

    Background and aims: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. Methods: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. Results: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6-15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2-12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. Conclusion: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up.

    @article{Derikx2021,
      abbr = {JCC},
      bibtex_show = {true},
      pdf = jjab100.pdf,
      title = {Effectiveness and safety of adalimumab biosimilar {SB5} in {IBD}: outcomes in originator to {SB5} switch, double biosimilar switch and bio-naieve SB5 observational cohorts},
      author = {Derikx, {Lauranne A A P} and Dolby, {Heather W} and Plevris, Nikolas and Lucaciu, Laura and Rees, {Caitlin S} and Lyons, Mathew and Siakavellas, {Spyros I} and Constantine-Cooke, Nathan and Jenkinson, Philip and Su, Shanna and O'Hare, Claire and Kirckpatrick, Laura and Merchant, {Lynne M} and Noble, Colin and Arnott, {Ian D} and Jones, Gareth-Rhys and Lees, {Charlie W}},
      year = {2021},
      month = jun,
      day = {5},
      doi = {10.1093/ecco-jcc/jjab100},
      language = {English},
      journal = {Journal of Crohn's and Colitis},
      issn = {1873-9946},
      publisher = {Elsevier},
      url = {https://doi.org/10.1093/ecco-jcc/jjab100}
    }