Skip to main content

Biologic disease-modifying anti-rheumatic drugs and patient-reported outcomes in axial SpA: a systematic review and a call for action

Abstract

This paper is to assess the efficacy of different biologic DMARDs (bDMARDs) on several patient-reported outcomes (PROs) in randomized controlled trials (RCT) in axial spondyloarthritis (axSpA). A systematic literature review (SLR) was performed. MEDLINE (May 1, 2018) was used with the filters “published in the last 10 years” and “humans.” The PICO criteria used were Patients: adults with radiographic axSpA (r-axSpA) or non-radiographic axSpA (nr-axSpA); Intervention: any bDMARD; Compararator: placebo (PBO)/any different drug; Outcome: the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Bath Ankylosing Spondylitis Functional Index (BASFI), the Ankylosing Spondylitis Quality of Life (ASQoL), the EuroQol-5D (EQ-5D), the Short Form 36 Health Survey physical component summary (SF36-PCS), the Short Form 36 Health Survey mental component summary (SF36-MCS), and the Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F). After screening 84 initial references and manually selecting other 9, 24 publications, assessing TNF inhibitors (TNFi) or IL17A inhibitors (IL17Ai) were selected. Four RCTs quantified the minimal clinical important difference (MCID) between treatment arms. Most of the RCTs compared the mean difference of PROs between different timepoints. Overall, the treatment arm was superior to the comparator. PROs were often underreported or highly heterogeneously presented. MCID was seldom mentioned. There is a need to raise the standard of care on SpA by aiming at remission and PRO associated improvements. In order to achieve this goal, the target must be clearly defined, reported, and tested.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A (1994) A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol 21:2286–2291

    CAS  PubMed  Google Scholar 

  2. 2.

    Calin A, Garrett S, Whitelock H, Kennedy LG, O'Hea J, Mallorie P, Jenkinson T (1994) A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol 21:2281–2285

    CAS  PubMed  Google Scholar 

  3. 3.

    Doward LC, Spoorenberg A, Cook SA, Whalley D, Helliwell PS, Kay LJ, McKenna SP, Tennant A, van der Heijde D, Chamberlain MA (2003) Development of the ASQoL: a quality of life instrument specific to ankylosing spondylitis. Ann Rheum Dis 62:20–26

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    EuroQol Group (1990) EuroQol--a new facility for the measurement of health-related quality of life. Health Policy 16:199–208

    Google Scholar 

  5. 5.

    Tang K, Beaton DE, Boonen A, Gignac MA, Bombardier C (2011) Measures of work disability and productivity: Rheumatoid Arthritis Specific Work Productivity Survey (WPS-RA), Workplace Activity Limitations Scale (WALS), Work Instability Scale for Rheumatoid Arthritis (RA-WIS), Work Limitations Questionnaire (WLQ), and Work Productivity And Activity Impairment Questionnaire (WPAI). Arthritis Care Res (Hoboken) 63(Suppl 11):S337–S349

    Google Scholar 

  6. 6.

    Jenkinson C, Coulter A, Wright L (1993) Short form 36 (SF36) health survey questionnaire: normative data for adults of working age. BMJ. 306:1437–1440

    CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Kiltz U, van der Heijde D, Boonen A, Akkoc N, Bautista-Molano W, Burgos-Vargas R, Wei JC, Chiowchanwisawakit P, Dougados M, Duruoz MT, Elzorkany BK, Gaydukova I, Gensler LS, Gilio M, Grazio S, Gu J, Inman RD, Kim TJ, Navarro-Compan V, Marzo-Ortega H, Ozgocmen S, Pimentel Dos Santos F, Schirmer M, Stebbings S, Van den Bosch FE, van Tubergen A, Braun J (2018) Measurement properties of the ASAS Health Index: results of a global study in patients with axial and peripheral spondyloarthritis. Ann Rheum Dis 77:1311–1317

    PubMed  Google Scholar 

  8. 8.

    Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E (1997) Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manag 13:63–74

    CAS  Google Scholar 

  9. 9.

    Machado P, Landewe R, Lie E, Kvien TK, Braun J, Baker D, van der Heijde D (2011) Ankylosing Spondylitis Disease Activity Score (ASDAS): defining cut-off values for disease activity states and improvement scores. Ann Rheum Dis 70:47–53

    PubMed  Google Scholar 

  10. 10.

    van der Heijde D, Ramiro S, Landewe R, Baraliakos X, Van den Bosch F, Sepriano A, Regel A, Ciurea A, Dagfinrud H, Dougados M, van Gaalen F, Geher P, van der Horst-Bruinsma I, Inman RD, Jongkees M, Kiltz U, Kvien TK, Machado PM, Marzo-Ortega H, Molto A, Navarro-Compan V, Ozgocmen S, Pimentel-Santos FM, Reveille J, Rudwaleit M, Sieper J, Sampaio-Barros P, Wiek D, Braun J (2017) 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis 76:978–991

    PubMed  Google Scholar 

  11. 11.

    van der Heijde D, Ramiro S, Landewé R, Baraliakos X, Van den Bosch F, Sepriano A, Regel A, Ciurea A, Dagfinrud H, Dougados M, van Gaalen F, Géher P, van der Horst-Bruinsma I, Inman RD, Jongkees M, Kiltz U, Kvien TK, Machado PM, Marzo-Ortega H, Molto A, Navarro-Compàn V, Ozgocmen S, Pimentel-Santos FM, Reveille J, Rudwaleit M, Sieper J, Sampaio-Barros P, Wiek D, Braun J (2017) 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis

  12. 12.

    Van den Bosch F, Kruithof E, Baeten D, De Keyser F, Mielants H, Veys EM (2000) Effects of a loading dose regimen of three infusions of chimeric monoclonal antibody to tumour necrosis factor alpha (infliximab) in spondyloarthropathy: an open pilot study. Ann Rheum Dis 59:428–433

    PubMed  PubMed Central  Google Scholar 

  13. 13.

    Jones A, Ciurtin C, Ismajli M, Leandro M, Sengupta R, Machado PM (2018) Biologics for treating axial spondyloarthritis. Expert Opin Biol Ther 18:641–652

    CAS  PubMed  Google Scholar 

  14. 14.

    Smolen JS, Schols M, Braun J, Dougados M, FitzGerald O, Gladman DD, Kavanaugh A, Landewe R, Mease P, Sieper J, Stamm T, Wit M, Aletaha D, Baraliakos X, Betteridge N, Bosch FVD, Coates LC, Emery P, Gensler LS, Gossec L, Helliwell P, Jongkees M, Kvien TK, Inman RD, McInnes IB, Maccarone M, Machado PM, Molto A, Ogdie A, Poddubnyy D, Ritchlin C, Rudwaleit M, Tanew A, Thio B, Veale D, Vlam K, van der Heijde D (2018) Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force. Ann Rheum Dis 77:3–17

    PubMed  Google Scholar 

  15. 15.

    Nota I, Drossaert CH, Taal E, Vonkeman HE, van de Laar MA (2014) Patient participation in decisions about disease modifying anti-rheumatic drugs: a cross-sectional survey. BMC Musculoskelet Disord 15:333

    PubMed  PubMed Central  Google Scholar 

  16. 16.

    Strand V, Singh JA (2017) Patient burden of axial spondyloarthritis. J Clin Rheumatol 23:383–391

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Jaeschke R, Singer J, Guyatt GH (1989) Measurement of health status. Ascertaining the minimal clinically important difference. Control Clin Trials 10:407–415

    CAS  PubMed  Google Scholar 

  18. 18.

    Rai SK, Yazdany J, Fortin PR, Avina-Zubieta JA (2015) Approaches for estimating minimal clinically important differences in systemic lupus erythematosus. Arthritis Res Ther 17:143

    PubMed  PubMed Central  Google Scholar 

  19. 19.

    Deodhar AA, Dougados M, Baeten DL, Cheng-Chung Wei J, Geusens P, Readie A, Richards HB, Martin R, Porter B (2016) Effect of Secukinumab on patient-reported outcomes in patients with active Ankylosing spondylitis: a phase III randomized trial (MEASURE 1). Arthritis Rheumatol. 68:2901–2910

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Zochling J (2011) Measures of symptoms and disease status in ankylosing spondylitis: Ankylosing Spondylitis Disease Activity Score (ASDAS), Ankylosing Spondylitis Quality of Life Scale (ASQoL), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Global Score (BAS-G), Bath Ankylosing Spondylitis Metrology Index (BASMI), Dougados Functional Index (DFI), and Health Assessment Questionnaire for the Spondylarthropathies (HAQ-S). Arthritis Care Res (Hoboken) 63(Suppl 11):S47–S58

    Google Scholar 

  21. 21.

    Rabin R, de Charro F (2001) EQ-5D: a measure of health status from the EuroQol group. Ann Med 33:337–343

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Cella D, Yount S, Sorensen M, Chartash E, Sengupta N, Grober J (2005) Validation of the functional assessment of chronic illness therapy fatigue scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 32:811–819

    PubMed  Google Scholar 

  23. 23.

    (2019) Current version of RoB 2. https://sites.google.com/site/riskofbiastool/welcome/rob-2-0-tool/current-version-of-rob-2

  24. 24.

    Dougados M, Braun J, Szanto S, Combe B, Elbaz M, Geher P, Thabut G, Leblanc V, Logeart I (2011) Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: results of a randomised double-blind placebo-controlled study (SPINE). Ann Rheum Dis 70:799–804

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Inman RD, Maksymowych WP, Group CS (2010) A double-blind, placebo-controlled trial of low dose infliximab in ankylosing spondylitis. J Rheumatol 37:1203–1210

    PubMed  Google Scholar 

  26. 26.

    Inman RD, Davis JC, Heijde D, Diekman L, Sieper J, Kim SI, Mack M, Han J, Visvanathan S, Xu Z, Hsu B, Beutler A, Braun J (2008) Efficacy and safety of golimumab in patients with ankylosing spondylitis: results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum 58:3402–3412

    CAS  PubMed  Google Scholar 

  27. 27.

    Deodhar A, Reveille JD, Harrison DD, Kim L, Lo KH, Leu JH, Hsia EC (2018) Safety and efficacy of Golimumab administered intravenously in adults with ankylosing spondylitis: results through week 28 of the GO-ALIVE study. J Rheumatol 45:341–348

    CAS  PubMed  Google Scholar 

  28. 28.

    Sieper J, Deodhar A, Marzo-Ortega H, Aelion JA, Blanco R, Jui-Cheng T, Andersson M, Porter B, Richards HB, Group MS (2016) Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 study. Ann Rheum Dis

  29. 29.

    Hu Z, Xu M, Li Q, Lin Z, Liao Z, Cao S, Wei Q, Zhang YL, Li T, Jin O, Huang J, Pan Y, Wu Y, Deng X, Gu J (2012) Adalimumab significantly reduces inflammation and serum DKK-1 level but increases fatty deposition in lumbar spine in active ankylosing spondylitis. Int J Rheum Dis 15:358–365

    CAS  PubMed  Google Scholar 

  30. 30.

    Maksymowych WP, Rahman P, Shojania K, Olszynski WP, Thomson GT, Ballal S, Wong RL, Inman RD, Group MS (2008) Beneficial effects of adalimumab on biomarkers reflecting structural damage in patients with ankylosing spondylitis. J Rheumatol 35:2030–2037

    CAS  PubMed  Google Scholar 

  31. 31.

    van der Heijde DM, Revicki DA, Gooch KL, Wong RL, Kupper H, Harnam N, Thompson C, Sieper J, Group AS (2009) Physical function, disease activity, and health-related quality-of-life outcomes after 3 years of adalimumab treatment in patients with ankylosing spondylitis. Arthritis Res Ther. 11:R124

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    van der Linden S, Valkenburg HA, Cats A (1984) Evaluation of diagnostic criteria for ankylosing spondylitis. A proposal for modification of the New York criteria. Arthritis Rheum 27:361–368

    PubMed  Google Scholar 

  33. 33.

    Sieper J, van der Heijde D, Dougados M, Maksymowych WP, Scott BB, Boice JA, Berd Y, Bergman G, Curtis S, Tzontcheva A, Huyck S, Weng HH (2015) A randomized, double-blind, placebo-controlled, sixteen-week study of subcutaneous golimumab in patients with active nonradiographic axial spondyloarthritis. Arthritis Rheumatol. 67:2702–2712

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Sieper J, van der Heijde D, Dougados M, Mease PJ, Maksymowych WP, Brown MA, Arora V, Pangan AL (2013) Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1). Ann Rheum Dis 72:815–822

    CAS  PubMed  Google Scholar 

  35. 35.

    Haibel H, Rudwaleit M, Listing J, Heldmann F, Wong RL, Kupper H, Braun J, Sieper J (2008) Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two. Arthritis Rheum 58:1981–1991

    CAS  PubMed  Google Scholar 

  36. 36.

    Dougados M, van der Heijde D, Sieper J, Braun J, Maksymowych WP, Citera G, Miceli-Richard C, Wei JC, Pedersen R, Bonin R, Rahman MU, Logeart I, Wajdula J, Koenig AS, Vlahos B, Alvarez D, Bukowski JF (2014) Symptomatic efficacy of etanercept and its effects on objective signs of inflammation in early nonradiographic axial spondyloarthritis: a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol 66:2091–2102

    CAS  PubMed  Google Scholar 

  37. 37.

    Sieper J, Kivitz A, van Tubergen A, Deodhar A, Coteur G, Woltering F, Landewe R (2015) Impact of Certolizumab Pegol on patient-reported outcomes in patients with axial spondyloarthritis. Arthritis Care Res (Hoboken). 67:1475–1480

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Dougados M, Wood E, Combe B, Schaeverbeke T, Miceli-Richard C, Berenbaum F, Koppiker N, Dubanchet A, Logeart I (2014) Evaluation of the nonsteroidal anti-inflammatory drug-sparing effect of etanercept in axial spondyloarthritis: results of the multicenter, randomized, double-blind, placebo-controlled SPARSE study. Arthritis Res Ther. 16:481

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Barkham N, Keen HI, Coates LC, O'Connor P, Hensor E, Fraser AD, Cawkwell LS, Bennett A, McGonagle D, Emery P (2009) Clinical and imaging efficacy of infliximab in HLA-B27-positive patients with magnetic resonance imaging-determined early sacroiliitis. Arthritis Rheum 60:946–954

    CAS  PubMed  Google Scholar 

  40. 40.

    van der Heijde D, Deodhar A, Braun J, Mack M, Hsu B, Gathany TA, Inman RD, Han C, investigators G-R (2014) The effect of golimumab therapy on disease activity and health-related quality of life in patients with ankylosing spondylitis: 2-year results of the GO-RAISE trial. J Rheumatol 41:1095–1103

    PubMed  Google Scholar 

  41. 41.

    Dougados M, Tsai WC, Saaibi DL, Bonin R, Bukowski J, Pedersen R, Vlahos B, Kotak S (2015) Evaluation of health outcomes with Etanercept treatment in patients with early nonradiographic axial Spondyloarthritis. J Rheumatol 42:1835–1841

    CAS  PubMed  Google Scholar 

  42. 42.

    Landewe R, Braun J, Deodhar A, Dougados M, Maksymowych WP, Mease PJ, Reveille JD, Rudwaleit M, van der Heijde D, Stach C, Hoepken B, Fichtner A, Coteur G, de Longueville M, Sieper J (2014) Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled phase 3 study. Ann Rheum Dis 73:39–47

    CAS  PubMed  Google Scholar 

  43. 43.

    Baeten D, Sieper J, Braun J, Baraliakos X, Dougados M, Emery P, Deodhar A, Porter B, Martin R, Andersson M, Mpofu S, Richards HB, Group MS (2015) Secukinumab, an interleukin-17A inhibitor, in Ankylosing spondylitis. N Engl J Med 373:2534–2548

    CAS  Google Scholar 

  44. 44.

    Marzo-Ortega H, Sieper J, Kivitz A, Blanco R, Cohen M, Martin R, Readie A, Richards HB, Porter B, Group MS (2017) Secukinumab and sustained improvement in signs and symptoms of patients with active ankylosing spondylitis through two years: results from a phase III study. Arthritis Care Res (Hoboken) 69:1020–1029

    CAS  Google Scholar 

  45. 45.

    Sieper J, Deodhar A, Marzo-Ortega H, Aelion JA, Blanco R, Jui-Cheng T, Andersson M, Porter B, Richards HB (2017) Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: results from the MEASURE 2 study. Ann Rheum Dis 76:571–592

    CAS  PubMed  Google Scholar 

  46. 46.

    Dougados M, van der Heijde D, Sieper J, Braun J, Citera G, Lenaerts J, van den Bosch F, Wei JC, Pedersen R, Bonin R, Jones H, Marshall L, Logeart I, Vlahos B, Bukowski JF, Maksymowych WP (2017) Effects of long-term Etanercept treatment on clinical outcomes and objective signs of inflammation in early nonradiographic axial spondyloarthritis: 104-week results from a randomized, Placebo-Controlled Study. Arthritis Care Res (Hoboken) 69:1590–1598

    CAS  Google Scholar 

  47. 47.

    Higgins JP, Savovic J, Page MJ, Sterne JA, on behalf of the ROB2 Development Group (2019) Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). https://drive.google.com/file/d/1xBzD1BeRrXH2DHg58fnTNKinTkX5SLEt/view

  48. 48.

    Nikiphorou E, Alunno A, Carmona L, Kouloumas M, Bijlsma J, Cutolo M (2017) Patient-physician collaboration in rheumatology: a necessity. RMD Open 3:e000499

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Kvien TK, Heiberg T, Hagen KB (2007) Minimal clinically important improvement/difference (MCII/MCID) and patient acceptable symptom state (PASS): what do these concepts mean? Ann Rheum Dis 66(Suppl 3):iii40–iii41

    PubMed  PubMed Central  Google Scholar 

  50. 50.

    Song F, Loke YK, Walsh T, Glenny AM, Eastwood AJ, Altman DG (2009) Methodological problems in the use of indirect comparisons for evaluating healthcare interventions: survey of published systematic reviews. BMJ. 338:b1147

    PubMed  PubMed Central  Google Scholar 

  51. 51.

    Van Tubergen A, Debats I, Ryser L, Londono J, Burgos-Vargas R, Cardiel MH, Landewe R, Stucki G, Van Der Heijde D (2002) Use of a numerical rating scale as an answer modality in ankylosing spondylitis-specific questionnaires. Arthritis Rheum 47:242–248

    PubMed  Google Scholar 

  52. 52.

    Bele S, Mohamed B, Chugh A, Haverman L, Santana MJ (2019) Impact of using patient-reported outcome measures in routine clinical care of paediatric patients with chronic conditions: a systematic review protocol. BMJ Open 9:e027354

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by Novartis Pharma Portugal. Funding was used to access all necessary scientific bibliography and cover meeting expenses. Novartis Pharma Portugal had no role in the collection, analysis, and interpretation of data, in the writing of the paper or in the decision to submit the paper for publication.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Santiago Rodrigues-Manica.

Ethics declarations

The manuscript does not contain clinical studies or patient data.

Conflict of interest

All authors except CC and JD declare collaborating and receiving fees from Novartis and other pharmaceutical companies either through participation in advisory board or consultancy, congress symposia, clinical trial conduct, investigator-initiated trials or grants. CC has no conflicts of interest. JD is an employee of Novartis Pharma Portugal.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

ESM 1

(DOCX 75 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rodrigues-Manica, S., Silva, J., Cruz-Machado, R. et al. Biologic disease-modifying anti-rheumatic drugs and patient-reported outcomes in axial SpA: a systematic review and a call for action. Clin Rheumatol 40, 33–41 (2021). https://doi.org/10.1007/s10067-020-05209-x

Download citation

Keywords

  • bDMARDs
  • Patient-reported outcomes
  • PROs
  • RCTs
  • Spondyloarthritis