Research Article| Volume 20, ISSUE 6, P716-727, June 2019

Discrete Trajectories of Resolving and Persistent Pain in People With Rheumatoid Arthritis Despite Undergoing Treatment for Inflammation: Results From Three UK Cohorts

  • Daniel F. McWilliams
    Address reprint requests to: Daniel F. McWilliams, University of Nottingham, Academic Rheumatology, Clinical Sciences Building, City Hospital, Nottingham NG5 1PB, UK.
    Arthritis Research UK Pain Centre and NIHR Nottingham Biomedical Research Centre, and

    Division of ROD, University of Nottingham, Nottingham, UK
    Search for articles by this author
  • Olivia Dawson
    Arthritis Research UK Pain Centre and NIHR Nottingham Biomedical Research Centre, and

    Division of ROD, University of Nottingham, Nottingham, UK
    Search for articles by this author
  • Adam Young
    Centre for Health Services & Clinical Research (CHSCR) & Postgraduate Medicine, University of Herts, Hatfield, UK
    Search for articles by this author
  • Patrick D.W. Kiely
    Department of Rheumatology, St Georges University Hospitals NHS Foundation Trust, London, UK
    Search for articles by this author
  • Eamonn Ferguson
    Arthritis Research UK Pain Centre and NIHR Nottingham Biomedical Research Centre, and

    School of Psychology, University of Nottingham, Nottingham, UK
    Search for articles by this author
  • David A. Walsh
    Arthritis Research UK Pain Centre and NIHR Nottingham Biomedical Research Centre, and

    Division of ROD, University of Nottingham, Nottingham, UK

    Department of Rheumatology, Sherwood Forest Hospitals NHS Foundation Trust, Sutton in Ashfield, UK

    Nottingham University Hospitals NHS Trust, Nottingham, UK
    Search for articles by this author
Published:January 15, 2019DOI:


      • Pain progression is heterogeneous in people with rheumatoid arthritis.
      • Persistent pain is predicted by high disability.
      • Even when inflammation resolves, the commonest trajectory is persistent pain.
      • Additional pain management might help people with rheumatoid arthritis.


      Rheumatoid arthritis (RA) is an example of human chronic inflammatory pain. Modern treatments suppress inflammation, yet pain remains a major problem for many people with RA. We hypothesized that discrete RA subgroups might display favorable or unfavorable pain trajectories when receiving treatment, and that baseline characteristics will predict trajectory allocation. Growth mixture modelling was used to identify discrete trajectories of Short Form-36 bodily pain scores during 3 years in 3 RA cohorts (Early RA Network (n = 683), British Society for Rheumatology Biologics Register Biologics (n = 7,090) and nonbiologics (n = 1,720) cohorts. Logistic regression compared baseline predictor variables between trajectories. The role of inflammation was examined in a subgroup analysis of people with normal levels of inflammatory markers after 3 years. The mean Short Form-36 bodily pain scores in each cohort improved but remained throughout 3 years of follow-up of >1 standard deviation worse than the UK general population average. Discrete persistent pain (59–79% of cohort participants) and resolving pain (19–27%) trajectories were identified in each cohort. In Early RA Network, a third trajectory displaying persistently low pain (23%) was also identified. In people with normal levels of inflammatory markers after 3 years, 65% were found to follow a persistent pain trajectory. When trajectories were compared, greater disability (adjusted odds ratio = 2.3–2.5 per unit baseline Health Assessment Questionnaire score) and smoking history (adjusted odds ratio = 1.6–1.8) were risk factors for persistent pain trajectories in each cohort. In conclusion, distinct trajectories indicate patient subgroups with very different pain prognosis during treatment for RA. Inflammation does not fully explain the pain trajectories, and noninflammatory factors as well as acute phase response predict which trajectory an individual will follow. Targeted treatments additional to those which suppress inflammation might reduce the long-term burden of arthritis pain.


      Immunosuppression decreases inflammation in RA, but pain outcomes are less favorable. Discrete persistent and resolving pain trajectories were identified after treatment, both in early and established RA. Smoking and greater disability at baseline predicted persistent pain. Identifying patient subgroups with a poor pain prognosis could enable adjunctive treatment to improve outcomes.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to The Journal of Pain
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Altawil R
        • Saevarsdottir S
        • Wedren S
        • Alfredsson L
        • Klareskog L
        • Lampa J
        Remaining pain in early rheumatoid arthritis patients treated with methotrexate.
        Arthritis Care Res. 2016; 68: 1061-1068
        • Arnett FC
        • Edworthy SM
        • Bloch DA
        • McShane DJ
        • Fries JF
        • Cooper NS
        • Healey LA
        • Kaplan SR
        • Liang MH
        • Luthra HS
        • Medsger Jr TS
        • Mitchell DM
        • Neustadt DH
        • Pinals RS
        • Schaller JG
        • Sharp JT
        • Wilder RL
        • Hunder GG
        The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis.
        Arthritis Rheum. 1988; 31: 315-324
        • Baillet A
        • Zeboulon N
        • Gossec L
        • Combescure C
        • Bodin LA
        • Juvin R
        • Dougados M
        • Gaudin P
        Efficacy of cardiorespiratory aerobic exercise in rheumatoid arthritis: Meta-analysis of randomized controlled trials.
        Arthritis Care Res. 2010; 62: 984-992
        • Barnabe C
        • Sun Y
        • Boire G
        • Hitchon CA
        • Haraoui B
        • Thorne JC
        • Tin D
        • van der Heijde D
        • Curtis JR
        • Jamal S
        • Pope JE
        • Keystone EC
        • Bartlett S
        • Bykerk VP
        • Investigators C
        Heterogeneous disease trajectories explain variable radiographic, function and quality of life outcomes in the Canadian Early Arthritis Cohort (CATCH).
        PLoS One. 2015; 10: e0135327
        • Bruce B
        • Fries JF
        The Stanford Health Assessment Questionnaire: A review of its history, issues, progress, and documentation.
        J Rheumatol. 2003; 30: 167-178
        • Carpenter L
        • Norton S
        • Nikiphorou E
        • Jayakumar K
        • McWilliams DF
        • Rennie KL
        • Dixey J
        • Kiely P
        • Walsh DA
        • Young A
        • Early Rheumatoid Arthritis S
        • the Early Rheumatoid Arthritis Network
        Reductions in radiographic progression in early rheumatoid arthritis over twenty-five years: Changing contribution from rheumatoid factor in two multicenter UK inception cohorts.
        Arthritis Care Res. 2017; 69: 1809-1817
        • Chang K
        • Yang SM
        • Kim SH
        • Han KH
        • Park SJ
        • Shin JI
        Smoking and rheumatoid arthritis.
        Int J Mol Sci. 2014; 15: 22279-22295
        • Christensen AW
        • Rifbjerg-Madsen S
        • Christensen R
        • Dreyer L
        • Boesen M
        • Ellegaard K
        • Bliddal H
        • Danneskiold-Samsoe B
        • Amris K
        Ultrasound Doppler but not temporal summation of pain predicts DAS28 response in rheumatoid arthritis: A prospective cohort study.
        Rheumatology (Oxford). 2016; 55: 1091-1098
        • Courvoisier DS
        • Alpizar-Rodriguez D
        • Gottenberg JE
        • Hernandez MV
        • Iannone F
        • Lie E
        • Santos MJ
        • Pavelka K
        • Turesson C
        • Mariette X
        • Choquette D
        • Hetland ML
        • Finckh A
        Rheumatoid arthritis patients after initiation of a new biologic agent: Trajectories of disease activity in a large multinational cohort study.
        EBioMedicine. 2016; 11: 302-306
        • Demmelmaier I
        • Dufour AB
        • Nordgren B
        • Opava CH
        Trajectories of physical activity over two years in persons with rheumatoid arthritis.
        Arthritis Care Res (Hoboken). 2016; 68: 1069-1077
        • Druce KL
        • Jones GT
        • Macfarlane GJ
        • Verstappen SM
        • Basu N
        The longitudinal course of fatigue in rheumatoid arthritis: Results from the Norfolk Arthritis Register.
        J Rheumatol. 2015; 42: 2059-2065
        • Dunlop DD
        • Song J
        • Semanik PA
        • Sharma L
        • Chang RW
        Physical activity levels and functional performance in the osteoarthritis initiative: A graded relationship.
        Arthritis Rheum. 2011; 63: 127-136
        • Ferguson E
        Personality is of central concern to understand health: Towards a theoretical model for health psychology.
        Health Psychol Rev. 2013; 7: S32-S70
        • Ferguson E
        • Lievens F
        Future directions in personality, occupational and medical selection: Myths, misunderstandings, measurement, and suggestions.
        Adv Health Sci Educ Theory Pract. 2017; 22: 387-399
        • Garwood W
        The Early Rheumatoid Arthritis Network (ERAN).
        Musculoskel Care. 2004; 2: 240-244
        • Goekoop-Ruiterman YP
        • de Vries-Bouwstra JK
        • Allaart CF
        • van Zeben D
        • Kerstens PJ
        • Hazes JM
        • Zwinderman AH
        • Ronday HK
        • Han KH
        • Westedt ML
        • Gerards AH
        • van Groenendael JH
        • Lems WF
        • van Krugten MV
        • Breedveld FC
        • Dijkmans BA
        Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial.
        Arthritis Rheum. 2008; 58: S126-S135
        • Hyrich KL
        • Symmons DP
        • Watson KD
        • Silman AJ
        Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register.
        Arthritis Rheum. 2006; 54: 1786-1794
      1. Hyrich KL, Watson KD, Lunt M, Symmons DP: Changes in disease characteristics and response rates among patients in the United Kingdom starting anti-tumour necrosis factor therapy for rheumatoid arthritis between 2001 and 2008. Rheumatology (Oxford) 50:117-123, 2011

        • James RJE
        • Walsh DA
        • Ferguson E
        General and disease-specific pain trajectories as predictors of social and political outcomes in arthritis and cancer.
        BMC Med. 2018; 16: 51
        • Jenkinson C
        • Stewart-Brown S
        • Petersen S
        • Paice C
        Assessment of the SF-36 version 2 in the United Kingdom.
        J Epidemiol Community Health. 1999; 53: 46-50
        • Joharatnam N
        • McWilliams DF
        • Wilson D
        • Wheeler M
        • Pande I
        • Walsh DA
        A cross-sectional study of pain sensitivity, disease-activity assessment, mental health, and fibromyalgia status in rheumatoid arthritis.
        Arthritis Res Ther. 2015; 17: 11
        • Jurgens MS
        • Overman CL
        • Jacobs JW
        • Geenen R
        • Cuppen BV
        • Marijnissen AC
        • Bijlsma JW
        • Welsing PM
        • Lafeber FP
        • van Laar JM
        • Utrecht Arthritis Cohort Study G
        Contribution of the subjective components of the disease activity score to the response to biologic treatment in rheumatoid arthritis.
        Arthritis Care Res (Hoboken). 2015; 67: 923-928
        • Kiely P
        • Walsh D
        • Williams R
        • Young A
        • Early Rheumatoid Arthritis N
        Outcome in rheumatoid arthritis patients with continued conventional therapy for moderate disease activity–the Early RA Network (ERAN).
        Rheumatology (Oxford, England). 2011; 50: 926-931
        • Lee AN
        • Beck CE
        • Hall M
        Rheumatoid factor and anti-CCP autoantibodies in rheumatoid arthritis: A review.
        Clin Lab Sci. 2008; 21: 15-18
        • Lee YC
        • Cui J
        • Lu B
        • Frits ML
        • Iannaccone CK
        • Shadick NA
        • Weinblatt ME
        • Solomon DH
        Pain persists in DAS28 rheumatoid arthritis remission but not in ACR/EULAR remission: A longitudinal observational study.
        Arthritis Res Ther. 2011; 13: R83
        • Little RJ
        • Wang Y
        Pattern-mixture models for multivariate incomplete data with covariates.
        Biometrics. 1996; 52: 98-111
        • McWilliams DF
        • Ferguson E
        • Young A
        • Kiely PD
        • Walsh DA
        Discordant inflammation and pain in early and established rheumatoid arthritis: Latent class analysis of Early Rheumatoid Arthritis Network and British Society for Rheumatology Biologics Register data.
        Arthritis Res Ther. 2016; 18: 295
        • McWilliams DF
        • Joharatnam N
        • Wilson D
        • Young A
        • Kiely P
        • Walsh DA
        Interpretation of DAS28 and its components in the assessment of inflammatory and non-inflammatory aspects of rheumatoid arthritis.
        BMC Rheumatol. 2018; 2: 8
        • McWilliams DF
        • Walsh DA
        Factors predicting pain and early discontinuation of tumour necrosis factor-alpha-inhibitors in people with rheumatoid arthritis: Results from the British society for rheumatology biologics register.
        BMC Musculoskelet Disord. 2016; 17: 337
        • McWilliams DF
        • Zhang W
        • Mansell JS
        • Kiely PD
        • Young A
        • Walsh DA
        Predictors of change in bodily pain in early rheumatoid arthritis: An inception cohort study.
        Arthritis Care Res (Hoboken). 2012; 64: 1505-1513
        • Muthen B
        • Asparouhov T
        • Hunter AM
        • Leuchter AF
        Growth modeling with nonignorable dropout: Alternative analyses of the STAR*D antidepressant trial.
        Psychol Methods. 2011; 16: 17-33
        • Neogi T
        • Guermazi A
        • Roemer F
        • Nevitt MC
        • Scholz J
        • Arendt-Nielsen L
        • Woolf C
        • Niu J
        • Bradley LA
        • Quinn E
        • Law LF
        Association of joint inflammation with pain sensitization in knee osteoarthritis: The Multicenter Osteoarthritis Study.
        Arthritis Rheumatol. 2016; 68: 654-661
        • NICE
        Rheumatoid arthritis—the management of rheumatoid arthritis in adults.
        HMSO, London2009
        • Norton S
        • Fu B
        • Scott DL
        • Deighton C
        • Symmons DP
        • Wailoo AJ
        • Tosh J
        • Lunt M
        • Davies R
        • Young A
        • Verstappen SM
        Health Assessment Questionnaire disability progression in early rheumatoid arthritis: Systematic review and analysis of two inception cohorts.
        Semin Arthritis Rheum. 2014; 44: 131-144
        • Norton S
        • Sacker A
        • Dixey J
        • Done J
        • Williams P
        • Young A
        Trajectories of functional limitation in early rheumatoid arthritis and their association with mortality.
        Rheumatology (Oxford, England). 2013; 52: 2016-2024
        • Norton S
        • Sacker A
        • Young A
        • Done J
        Distinct psychological distress trajectories in rheumatoid arthritis: Findings from an inception cohort.
        J Psychosom Res. 2011; 71: 290-295
        • Odegard S
        • Finset A
        • Mowinckel P
        • Kvien TK
        • Uhlig T
        Pain and psychological health status over a 10-year period in patients with recent onset rheumatoid arthritis.
        Ann Rheum Dis. 2007; 66: 1195-1201
        • Pollard LC
        • Ibrahim F
        • Choy EH
        • Scott DL
        Pain thresholds in rheumatoid arthritis: The effect of tender point counts and disease duration.
        J Rheumatol. 2012; 39: 28-31
        • Pollard LC
        • Kingsley GH
        • Choy EH
        • Scott DL
        Fibromyalgic rheumatoid arthritis and disease assessment.
        Rheumatology (Oxford). 2010; 49: 924-928
        • Prothero L
        • Barley E
        • Galloway J
        • Georgopoulou S
        • Sturt J
        The evidence base for psychological interventions for rheumatoid arthritis: A systematic review of reviews.
        Int J Nurs Stud. 2018; 82: 20-29
        • Shi Y
        • Weingarten TN
        • Mantilla CB
        • Hooten WM
        • Warner DO
        Smoking and pain: Pathophysiology and clinical implications.
        Anesthesiology. 2010; 113: 977-992
        • Shiff NJ
        • Tupper S
        • Oen K
        • Guzman J
        • Lim H
        • Lee CH
        • Bryce R
        • Huber AM
        • Boire G
        • Dancey P
        • Feldman B
        • Laxer R
        • Miettunen P
        • Schmeling H
        • Watanabe Duffy K
        • Levy DM
        • Turvey S
        • Bolaria R
        • Bruns A
        • Cabral DA
        • Campillo S
        • Chedeville G
        • Feldman DE
        • Haddad E
        • Houghton K
        • Johnson N
        • Jurencak R
        • Lang B
        • Larche M
        • Morishita K
        • Ramsey S
        • Roth J
        • Schneider R
        • Scuccimarri R
        • Spiegel L
        • Stringer E
        • Tse SM
        • Yeung R
        • Duffy CM
        • Tucker LB
        Trajectories of pain severity in juvenile idiopathic arthritis: Results from the Research in Arthritis in Canadian Children Emphasizing Outcomes cohort.
        Pain. 2018; 159: 57-66
        • Siemons L
        • Ten Klooster PM
        • Vonkeman HE
        • Glas CA
        • Van de Laar M
        Distinct trajectories of disease activity over the first year in early rheumatoid arthritis patients following a treat-to-target strategy.
        Arthritis Care Res (Hoboken). 2014; 66: 625-630
        • Silman A
        • Symmons D
        • Scott DG
        • Griffiths I
        British Society for Rheumatology Biologics Register.
        Ann Rheum Dis. 2003; 62: ii28-29
        • Ton E
        • Bakker MF
        • Verstappen SM
        • Ter Borg EJ
        • van Albada-Kuipers IA
        • Schenk Y
        • van der Veen MJ
        • Bijlsma JW
        • Jacobs JW
        Look beyond the disease activity score of 28 joints (DAS28): Tender points influence the DAS28 in patients with rheumatoid arthritis.
        J Rheumatol. 2012; 39: 22-27
      2. Van Riel PL: Disease activity score in rheumatoid arthritis. 2018. Available at:; Accessed September 10, 2018

        • Verhoeven F
        • Tordi N
        • Prati C
        • Demougeot C
        • Mougin F
        • Wendling D
        Physical activity in patients with rheumatoid arthritis.
        Joint Bone Spine. 2016; 83: 265-270
        • Ware JE
        • Snow KK
        • Kosinski M
        SF-36 health survey: Manual and interpretation guide.
        2nd ed. QualityMetric Inc, Lincoln, RI2000
        • Wolfe F
        • Hauser W
        • Hassett AL
        • Katz RS
        • Walitt BT
        The development of fibromyalgia–I: Examination of rates and predictors in patients with rheumatoid arthritis (RA).
        Pain. 2011; 152: 291-299