PMID- 38072179
OWN - NLM
STAT- MEDLINE
DCOM- 20240311
LR  - 20240311
IS  - 1878-5921 (Electronic)
IS  - 0895-4356 (Linking)
VI  - 166
DP  - 2024 Feb
TI  - Developing and externally validating multinomial prediction models for 
      methotrexate treatment outcomes in patients with rheumatoid arthritis: results 
      from an international collaboration.
PG  - 111239
LID - S0895-4356(23)00335-9 [pii]
LID - 10.1016/j.jclinepi.2023.111239 [doi]
AB  - OBJECTIVES: In rheumatology, there is a clinical need to identify patients at 
      high risk (>50%) of not responding to the first-line therapy methotrexate (MTX) 
      due to lack of disease control or discontinuation due to adverse events (AEs). 
      Despite this need, previous prediction models in this context are at high risk of 
      bias and ignore AEs. Our objectives were to (i) develop a multinomial model for 
      outcomes of low disease activity and discontinuing due to AEs 6 months after 
      starting MTX, (ii) update prognosis 3-month following treatment initiation, and 
      (iii) externally validate these models. STUDY DESIGN AND SETTING: A multinomial 
      model for low disease activity (submodel 1) and discontinuing due to AEs 
      (submodel 2) was developed using data from the UK Rheumatoid Arthritis Medication 
      Study, updated using landmarking analysis, internally validated using 
      bootstrapping, and externally validated in the Norwegian Disease-Modifying 
      Antirheumatic Drug register. Performance was assessed using calibration 
      (calibration-slope and calibration-in-the-large), and discrimination 
      (concordance-statistic and polytomous discriminatory index). RESULTS: The 
      internally validated model showed good calibration in the development setting 
      with a calibration-slope of 1.01 (0.87, 1.14) (submodel 1) and 0.83 (0.30, 1.34) 
      (submodel 2), and moderate discrimination with a c-statistic of 0.72 (0.69, 0.74) 
      and 0.53 (0.48, 0.59), respectively. Predictive performance decreased after 
      external validation (calibration-slope 0.78 (0.64, 0.93) (submodel 1) and 0.86 
      (0.34, 1.38) (submodel 2)), which may be due to differences in disease-specific 
      characteristics and outcome prevalence. CONCLUSION: We addressed previously 
      identified methodological limitations of prediction models for outcomes of MTX 
      therapy. The multinomial approach predicted outcomes of disease activity more 
      accurately than AEs, which should be addressed in future work to aid 
      implementation into clinical practice.
CI  - Copyright (c) 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
FAU - Gehringer, Celina K
AU  - Gehringer CK
AD  - Division of Musculoskeletal and Dermatological Sciences, Centre for Epidemiology 
      Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, 
      Manchester, UK; Centre for Biostatistics, Manchester Academic Health Science 
      Centre, University of Manchester, Manchester, UK. Electronic address: 
      celina.gehringer@postgrad.manchester.ac.uk.
FAU - Martin, Glen P
AU  - Martin GP
AD  - Division of Informatics, Imaging and Data Sciences, Centre for Health 
      Informatics, University of Manchester, Manchester, UK.
FAU - Hyrich, Kimme L
AU  - Hyrich KL
AD  - Division of Musculoskeletal and Dermatological Sciences, Centre for Epidemiology 
      Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, 
      Manchester, UK; NIHR Manchester Biomedical Research Centre, Manchester University 
      NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
FAU - Verstappen, Suzanne M M
AU  - Verstappen SMM
AD  - Division of Musculoskeletal and Dermatological Sciences, Centre for Epidemiology 
      Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, 
      Manchester, UK; NIHR Manchester Biomedical Research Centre, Manchester University 
      NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
FAU - Sexton, Joseph
AU  - Sexton J
AD  - Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), 
      Diakonhjemmet Hospital, Oslo, Norway.
FAU - Kristianslund, Eirik K
AU  - Kristianslund EK
AD  - Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), 
      Diakonhjemmet Hospital, Oslo, Norway.
FAU - Provan, Sella A
AU  - Provan SA
AD  - Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), 
      Diakonhjemmet Hospital, Oslo, Norway.
FAU - Kvien, Tore K
AU  - Kvien TK
AD  - Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), 
      Diakonhjemmet Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, 
      Oslo, Norway.
FAU - Sergeant, Jamie C
AU  - Sergeant JC
AD  - Division of Musculoskeletal and Dermatological Sciences, Centre for Epidemiology 
      Versus Arthritis, Centre for Musculoskeletal Research, University of Manchester, 
      Manchester, UK; Centre for Biostatistics, Manchester Academic Health Science 
      Centre, University of Manchester, Manchester, UK.
LA  - eng
GR  - MR/T025085/1/MRC_/Medical Research Council/United Kingdom
PT  - Journal Article
DEP - 20231208
PL  - United States
TA  - J Clin Epidemiol
JT  - Journal of clinical epidemiology
JID - 8801383
RN  - YL5FZ2Y5U1 (Methotrexate)
RN  - 0 (Antirheumatic Agents)
SB  - IM
MH  - Humans
MH  - Methotrexate/therapeutic use
MH  - *Arthritis, Rheumatoid/drug therapy
MH  - *Antirheumatic Agents/therapeutic use
MH  - Treatment Outcome
MH  - Prognosis
OTO - NOTNLM
OT  - Calibration
OT  - External validation
OT  - Methotrexate
OT  - Multinomial prediction model
OT  - Recalibration
OT  - Risk prediction
COIS- Declaration of competing interest KLH has received speaker honoraria from AbbVie 
      and grant income from BMS and Pfizer. TKK has received fees for speaking from 
      Janssen, Sandoz, Grunenthal, and UCB; fees for consulting from AbbVie, Galapagos, 
      Janssen, Pfizer, and Sandoz; research funding to Diakonhjemmet Hospital from 
      AbbVie, BMS, Novartis, Pfizer, and UCB.
EDAT- 2023/12/11 00:42
MHDA- 2024/03/11 06:44
CRDT- 2023/12/10 19:29
PHST- 2023/10/05 00:00 [received]
PHST- 2023/11/23 00:00 [revised]
PHST- 2023/12/05 00:00 [accepted]
PHST- 2024/03/11 06:44 [medline]
PHST- 2023/12/11 00:42 [pubmed]
PHST- 2023/12/10 19:29 [entrez]
AID - S0895-4356(23)00335-9 [pii]
AID - 10.1016/j.jclinepi.2023.111239 [doi]
PST - ppublish
SO  - J Clin Epidemiol. 2024 Feb;166:111239. doi: 10.1016/j.jclinepi.2023.111239. Epub 
      2023 Dec 8.