Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

Reflections on ‘older’ drugs: learning new lessons in rheumatology

Nature Reviews Rheumatology volume 16, pages 179–183 (2020)Cite this article

Subjects

Abstract

The management of rheumatic and musculoskeletal diseases has transformed over two decades of exciting discoveries regarding pathogenesis and innovative drug development. The introduction of sophisticated immunomodulatory therapies has given renewed hope to many patients, but notable challenges remain within the field of rheumatology. Before the advent of biologic therapies, conventional synthetic DMARDs (csDMARDs) provided effective disease control for some patients, although a comprehensive understanding of the mechanisms by which these drugs exert their effects remained elusive. Reflecting upon the efficacy and mechanisms of action of csDMARDs can provide intriguing insights. First, contemplating past approaches brings our remarkable current approaches concerning pathogenesis-driven discovery and drug development into sharper focus. Second, increased understanding of the mode of action of these older drugs might in turn provide exciting opportunities for the understanding of disease and for the development of future therapies.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Drug discovery in rheumatic musculoskeletal diseases.

Similar content being viewed by others

References

  1. Dadoun, S. et al. Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine 80, 29–33 (2013).

    Article  PubMed  Google Scholar 

  2. Eshed, I. et al. Tenosynovitis of the flexor tendons of the hand detected by MRI: an early indicator of rheumatoid arthritis. Rheumatology 48, 887–891 (2009).

    Article  PubMed  Google Scholar 

  3. Taylor, P., Gartemann, J., Hsieh, J. & Creeden, J. A systematic review of serum biomarkers anti-cyclic citrullinated peptide and rheumatoid factor as tests for rheumatoid arthritis. Autoimmune Dis. 2011, 815038 (2011).

    PubMed  PubMed Central  Google Scholar 

  4. Grigor, C. et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 364, 263–269 (2004).

    Article  PubMed  Google Scholar 

  5. Buer, J. K. A history of the term “DMARD”. Inflammopharmacology 23, 163–171 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Fraser, T. N. Gold treatment in rheumatoid arthritis. Ann. Rheum. Dis. 4, 71–75 (1945).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Forestier, J. The treatment of rheumatoid arthritis with gold salts injections. Lancet 219, 441–444 (1932).

    Article  Google Scholar 

  8. Weinblatt, M. E. Methotrexate in rheumatoid arthritis: a quarter century of development. Trans. Am. Clin. Climatol. Assoc. 124, 16–25 (2013).

    PubMed  PubMed Central  Google Scholar 

  9. Upchurch, K. S. & Kay, J. Evolution of treatment for rheumatoid arthritis. Rheumatology 51 (Suppl. 6), vi28–vi36 (2012).

    CAS  PubMed  Google Scholar 

  10. Whitehouse, M. W. Anti-inflammatory glucocorticoid drugs: reflections after 60 years. Inflammopharmacology 19, 1–19 (2011).

    Article  CAS  PubMed  Google Scholar 

  11. Hardy, R. S., Raza, K. & Cooper, M. S. Therapeutic glucocorticoids: mechanisms of actions in rheumatic diseases. Nat. Rev. Rheumatol. 16, 133–144 (2020).

    Article  PubMed  Google Scholar 

  12. Cronstein, B. N. & Aune, T. M. Methotrexate and its mechanisms of action in inflammatory arthritis. Nat. Rev. Rheumatol. 16, 145–154 (2020).

    Article  CAS  PubMed  Google Scholar 

  13. Schrezenmeier, E. & Dörner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology. Nat. Rev. Rheumatol. 16, 155–166 (2020).

    Article  CAS  PubMed  Google Scholar 

  14. Broen, J. C. A. & van Laar, J. M. Mycophenolate mofetil, azathioprine and tacrolimus: mechanisms in rheumatology. Nat. Rev. Rheumatol. 16, 167–178 (2020).

    Article  CAS  PubMed  Google Scholar 

  15. Rodnan, G. P. & Benedek, T. G. The early history of antirheumatic drugs. Arthritis Rheum. 13, 145–165 (1970).

    Article  CAS  PubMed  Google Scholar 

  16. Burns, C. M. The history of cortisone discovery and development. Rheum. Dis. Clin. North Am. 42, 1–14 (2016).

    Article  PubMed  Google Scholar 

  17. Verhoeven, M. M. et al. Initiating tocilizumab, with or without methotrexate, compared with starting methotrexate with prednisone within step-up treatment strategies in early rheumatoid arthritis: an indirect comparison of effectiveness and safety of the U-Act-Early and CAMERA-II treat-to-target trials. Ann. Rheum. Dis. 78, 1333–1338 (2019).

    Article  PubMed  Google Scholar 

  18. Firestein, G. S. & McInnes, I. B. Immunopathogenesis of rheumatoid arthritis. Immunity 46, 183–196 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).

    Article  CAS  PubMed  Google Scholar 

  20. Veale, D. J. & Fearon, U. The pathogenesis of psoriatic arthritis. Lancet 391, 2273–2284 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Schett, G. et al. Enthesitis: from pathophysiology to treatment. Nat. Rev. Rheumatol. 13, 731–741 (2017).

    Article  CAS  PubMed  Google Scholar 

  22. McGonagle, D. Enthesitis: an autoinflammatory lesion linking nail and joint involvement in psoriatic disease. J. Eur. Acad. Dermatol. Venereol. 23 (Suppl. II), 9–13 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Bulpitt, K. J. Biologic therapies in rheumatoid arthritis. Curr. Rheumatol. Rep. 1, 157–163 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Burmester, G. R., Bijlsma, J. W. J., Cutolo, M. & McInnes, I. B. Managing rheumatic and musculoskeletal diseases – past, present and future. Nat. Rev. Rheumatol. 13, 443–448 (2017).

    Article  CAS  PubMed  Google Scholar 

  25. Barturen, G., Beretta, L., Cervera, R., van Vollenhoven, R. & Alarcón-Riquelme, M. E. Moving towards a molecular taxonomy of autoimmune rheumatic diseases. Nat. Rev. Rheumatol. 14, 75–93 (2018).

    Article  CAS  PubMed  Google Scholar 

  26. Orange, D. E. et al. Identification of three rheumatoid arthritis disease subtypes by machine learning integration of synovial histologic features and RNA sequencing data. Arthritis Rheumatol. 70, 690–701 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Orr, C. et al. Synovial tissue research: a state-of-the-art review. Nat. Rev. Rheumatol. 13, 463–475 (2017).

    Article  PubMed  Google Scholar 

  28. Stephenson, W. et al. Single-cell RNA-seq of rheumatoid arthritis synovial tissue using low-cost microfluidic instrumentation. Nat. Commun. 9, 791 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. ISRCTN registry. Stratification of biologic therapies for rheumatoid arthritis by pathobiology. ISRCTN http://www.isrctn.com/ISRCTN10618686 (2019).

  30. Winthrop, K. L. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat. Rev. Rheumatol. 13, 234–243 (2017).

    Article  CAS  PubMed  Google Scholar 

  31. Meier, F. M. & McInnes, I. B. Small-molecule therapeutics in rheumatic arthritis: scientific rationale, efficacy and safety. Best. Pract. Res. Clin. Rheumatol. 28, 605–624 (2014).

    Article  PubMed  Google Scholar 

  32. Schwartz, D. M. et al. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat. Rev. Drug Discov. 17, 843–862 (2017).

    Article  CAS  Google Scholar 

  33. Tasaki, S. et al. Multi-omics monitoring of drug response in rheumatoid arthritis in pursuit of molecular remission. Nat. Commun. 9, 2755 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mizoguchi, F. et al. Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis. Nat. Commun. 9, 789 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Croft, A. P. et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 570, 246–251 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Pilgaard, T., Hagelund, L., Stallknecht, S. E., Jensen, H. H. & Esbensen, B. A. Severity of fatigue in people with rheumatoid arthritis, psoriatic arthritis and spondyloarthritis – results of a cross-sectional study. PLoS One 14, e0218831 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Baker, K. F. et al. Predicting drug-free remission in rheumatoid arthritis – a prospective interventional cohort study. J. Autoimmun. 105, 102298 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Buch, M. H. Defining refractory rheumatoid arthritis. Ann. Rheum. Dis. 77, 966–969 (2018).

    Article  CAS  PubMed  Google Scholar 

  39. Radner, H., Yoshida, K., Smolen, J. S. & Solomon, D. H. Multimorbidity and rheumatic conditions — enhancing the concept of comorbidity. Nat. Rev. Rheumatol. 10, 252–256 (2014).

    Article  PubMed  Google Scholar 

  40. Nunes, B. P., Flores, T. R., Mielke, G. I., Thumé, E. & Facchini, L. A. Multimorbidity and mortality in older adults: a systematic review and meta-analysis. Arch. Gerontol. Geriatr. 67, 130–138 (2016).

    Article  PubMed  Google Scholar 

  41. Michaud, K. & Wolfe, F. Comorbidities in rheumatoid arthritis. Best. Pract. Res. Clin. Rheumatol. 21, 885–906 (2007).

    Article  PubMed  Google Scholar 

  42. Solomon, D. H. et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann. Rheum. Dis. 65, 1608–1612 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huscher, D. et al. Clinical presentation, burden of disease and treatment in young-onset and late-onset rheumatoid arthritis: a matched-pairs analysis taking age and disease duration into account. Clin. Exp. Rheumatol. 31, 256–262 (2013).

    PubMed  Google Scholar 

  44. Robertson, J. et al. Interleukin-6 blockade raises LDL via reduced catabolism rather than via increased synthesis: a cytokine-specific mechanism for cholesterol changes in rheumatoid arthritis. Ann. Rheum. Dis. 76, 1949–1952 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. McInnes, I. B. et al. Effect of interleukin-6 receptor blockade on surrogates of vascular risk in rheumatoid arthritis: MEASURE, a randomised, placebo-controlled study. Ann. Rheum. Dis. 74, 694–702 (2015).

    Article  CAS  PubMed  Google Scholar 

  46. Gabay, C. et al. Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis. Ann. Rheum. Dis. 75, 1806–1812 (2016).

    Article  CAS  PubMed  Google Scholar 

  47. Mangoni, A. A. et al. Repurposing existing drugs for cardiovascular risk management: a focus on methotrexate. Drugs Context 7, 212557 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Everett, B. M. et al. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation 139, 1289–1299 (2019).

    Article  CAS  PubMed  Google Scholar 

  49. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  50. Ridker, P. M. et al. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380, 752–762 (2019).

    Article  CAS  PubMed  Google Scholar 

  51. Norheim, K. B., Jonsson, G. & Omdal, R. Biological mechanisms of chronic fatigue. Rheumatology 50, 1009–1018 (2011).

    Article  CAS  PubMed  Google Scholar 

  52. Phillips, K. & Clauw, D. J. Central pain mechanisms in the rheumatic diseases: future directions. Arthritis Rheum. 65, 291–302 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  53. Breedveld, F. C. Appropriate and effective management of rheumatoid arthritis. Ann. Rheum. Dis. 63, 627–633 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Fleischmann, R. M. et al. Safety and effectiveness of upadacitinib or adalimumab plus methotrexate in patients with rheumatoid arthritis over 48 weeks with switch to alternate therapy in patients with insufficient response. Ann. Rheum. Dis. 78, 1454–1462 (2019).

    Article  PubMed  Google Scholar 

  55. Rendas-Baum, R. et al. Evaluating the efficacy of sequential biologic therapies for rheumatoid arthritis patients with an inadequate response to tumor necrosis factor-α inhibitors. Arthritis Res. Ther. 13, R25 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dakin, S. G. et al. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat. Rev. Rheumatol. 14, 714–726 (2018).

    Article  PubMed  Google Scholar 

  57. Bell, G. M. et al. Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann. Rheum. Dis. 76, 227–234 (2016).

    Article  PubMed  Google Scholar 

  58. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01352858 (2018).

  59. Rosenzwajg, M. et al. Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial. Ann. Rheum. Dis. 78, 209–217 (2019).

    Article  CAS  PubMed  Google Scholar 

  60. Gravallese, E. M. & Walsh, N. C. Repair of erosion in RA – shifting the balance to formation. Nat. Rev. Rheumatol. 7, 626–628 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  61. Ringe, J. & Sittinger, M. Tissue engineering in the rheumatic diseases. Arthritis Res. Ther. 11, 211 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Goh, E. L., Lou, W. C. N., Chidambaram, S. & Ma, S. Joint distraction for knee osteoarthritis: protocol for a systematic review and meta-analysis. Syst. Rev. 7, 162 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Jones, I. A., Togashi, R., Wilson, M. L., Heckmann, N. & Vangsness, C. T. Intra-articular treatment options for knee osteoarthritis. Nat. Rev. Rheumatol. 15, 77–90 (2018).

    Article  Google Scholar 

  64. Friedman, B. & Cronstein, B. Methotrexate mechanism in treatment of rheumatoid arthritis. Joint Bone Spine 86, 301–307 (2019).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    S. A. Kerrigan & I. B. McInnes

Authors
  1. S. A. Kerrigan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. I. B. McInnes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to I. B. McInnes.

Ethics declarations

Competing interests

I.B.M. declares that he has received honoraria and/or research funding from Abbvie, BMS, Boerhinger, Celgene, Janssen, Lilly, Novartis, Pfizer and UCB. S.A.K. declares that he has no competing interests

Additional information

Peer review information

Nature Reviews Rheumatology thanks J. Bijlsma and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kerrigan, S.A., McInnes, I.B. Reflections on ‘older’ drugs: learning new lessons in rheumatology. Nat Rev Rheumatol 16, 179–183 (2020). https://doi.org/10.1038/s41584-020-0375-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-020-0375-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing