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.

  • Review Article
  • Published:

Drug repurposing to improve treatment of rheumatic autoimmune inflammatory diseases

Nature Reviews Rheumatology volume 16, pages 32–52 (2020)Cite this article

Subjects

Abstract

The past century has been characterized by intensive efforts, within both academia and the pharmaceutical industry, to introduce new treatments to individuals with rheumatic autoimmune inflammatory diseases (RAIDs), often by ‘borrowing’ treatments already employed in one RAID or previously used in an entirely different disease, a concept known as drug repurposing. However, despite sharing some clinical manifestations and immune dysregulation, disease pathogenesis and phenotype vary greatly among RAIDs, and limited understanding of their aetiology has made repurposing drugs for RAIDs challenging. Nevertheless, the past century has been characterized by different ‘waves’ of repurposing. Early drug repurposing occurred in academia and was based on serendipitous observations or perceived disease similarity, often driven by the availability and popularity of drug classes. Since the 1990s, most biologic therapies have been developed for one or several RAIDs and then tested among the others, with varying levels of success. The past two decades have seen data-driven repurposing characterized by signature-based approaches that rely on molecular biology and genomics. Additionally, many data-driven strategies employ computational modelling and machine learning to integrate multiple sources of data. Together, these repurposing periods have led to advances in the treatment for many RAIDs.

Key points

  • Repurposing drugs for and among rheumatic autoimmune inflammatory diseases (RAIDs) is difficult because of limitations in knowledge surrounding the pathogenesis of these diseases.

  • Clinical and academic-driven drug repurposing was critical for the early identification of treatments for RAIDs.

  • High costs and increased regulation shifted drug repurposing from primarily academia to pharmaceutical companies.

  • Computational repurposing has the ability to elucidate previously unknown drug mechanisms of action and off-target effects.

  • Genomic and genetic data can identify new pathways and targets for drug repurposing.

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: Historical periods of drug class-based repurposing in RAIDs.
Fig. 2: Successful drug repurposing among RAIDs.
Fig. 3: Computational and data-driven advances have changed the landscape of drug repurposing.

Similar content being viewed by others

References

  1. Elliott, M. J. et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheumatol. 36, 1681–1690 (1993).

    CAS  Google Scholar 

  2. Weinblatt, M. E. et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N. Engl. J. Med. 340, 253–259 (1999).

    CAS  PubMed  Google Scholar 

  3. Kalunian, K. C. et al. A Phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196–202 (2016).

    PubMed  Google Scholar 

  4. Furie, R. et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheumatol. 63, 3918–3930 (2011).

    CAS  Google Scholar 

  5. Mease, P. J. et al. Etanercept treatment of psoriatic arthritis: safety, efficacy, and effect on disease progression. Arthritis Rheumatol. 50, 2264–2272 (2004).

    CAS  Google Scholar 

  6. McInnes, I. B. et al. Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 386, 1137–1146 (2015).

    CAS  PubMed  Google Scholar 

  7. Vivino, F. B. et al. New treatment guidelines for Sjögren’s disease. Rheum. Dis. Clin. North. Am. 42, 531–551 (2016).

    PubMed  PubMed Central  Google Scholar 

  8. Johr, C. R. & Vivino, F. B. Biologic therapy in the treatment of Sjögren’s syndrome: a clinical perspective. Curr. Treat. Options Rheumatol. 4, 85–98 (2018).

    Google Scholar 

  9. Mahieu, M., Strand, V., Simon, L., Lipsky, P. & Ramsey-Goldman, R. A critical review of clinical trials in systemic lupus erythematosus. Lupus 25, 1122–1140 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Hruskova, Z. & Tesar, V. Lessons learned from the failure of several recent trials with biologic treatment in systemic lupus erythematosus. Expert Opin. Biol. Ther. 18, 989–996 (2018).

    CAS  PubMed  Google Scholar 

  11. Touma, Z. & Gladman, D. D. Current and future therapies for SLE: obstacles and recommendations for the development of novel treatments. Lupus Sci. Med. 4, e000239 (2017).

    PubMed  PubMed Central  Google Scholar 

  12. Langedijk, J., Mantel-Teeuwisse, A. K., Slijkerman, D. S. & Schutjens, M.-H. D. B. Drug repositioning and repurposing: terminology and definitions in literature. Drug Discov. Today 20, 1027–1034 (2015).

    PubMed  Google Scholar 

  13. Papapetropoulos, A. & Szabo, C. Inventing new therapies without reinventing the wheel: the power of drug repurposing. Br. J. Pharmacol. 175, 165–167 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Ashburn, T. T. & Thor, K. B. Drug repositioning: identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 3, 673–683 (2004).

    CAS  PubMed  Google Scholar 

  15. Nosengo, N. Can you teach old drugs new tricks? Nature 534, 314–316 (2016).

    PubMed  Google Scholar 

  16. Allison, M. NCATS launches drug repurposing program. Nat. Biotechnol. 30, 571–572 (2012).

    CAS  PubMed  Google Scholar 

  17. Norn, S., Permin, H., Kruse, P. R. & Kruse, E. History of gold-with Danish contribution to tuberculosis and rheumatoid arthritis [article in Danish]. Dan. Medicinhist. Arbog 39, 59–80 (2011).

    PubMed  Google Scholar 

  18. Møllgaard, H. Some of the principal questions in chemotherapy with special regard to heavy metals. Proc. R. Soc. Med. 20, 787 (1927).

    PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Empire Rheumatism Council. Gold therapy in rheumatoid arthritis. A multicentre controlled trial conducted by the Research Subcommittee. Bull. Rheum. Dis. 11, 235–238 (1960).

    Google Scholar 

  21. Research Sub-Committee Of The Empire Rheumatism Council. Gold therapy in rheumatoid arthritis: final report of a multicentre controlled trial. Ann. Rheum. Dis. 20, 315–334 (1961).

    Google Scholar 

  22. Wenger, M. E., Alexander, S., Bland, J. H. & Blechman, W. J. Auranofin versus placebo in the treatment of rheumatoid arthritis. Am. J. Med. 75, 123–127 (1983).

    CAS  PubMed  Google Scholar 

  23. Swift, H. F. & Brown, T. M. P. Pathogenic pleuropneumonia-like microorganisms from acute rheumatic exudates and tissues. Science 89, 271–272 (1939).

    CAS  PubMed  Google Scholar 

  24. Kloppenburg, M., Breedveld, F. C., Terwiel, J. P., Mallee, C. & Dijkmans, B. A. Minocycline in active rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheumatol. 37, 629–636 (1994).

    CAS  Google Scholar 

  25. Tilley, B. C. et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann. Intern. Med. 122, 81–89 (1995).

    CAS  PubMed  Google Scholar 

  26. Svartz, N. Salazopyrin, a new sulfanilamide preparation. A. Therapeutic results in rheumatic polyarthritis. B. Therapeutic results in ulcerative colitis. C. Toxic manifestations in treatment with sulfanilamide preparations. Acta Med. Scand. 110, 577–598 (1942).

    Google Scholar 

  27. O’Dell, J. R. et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N. Engl. J. Med. 334, 1287–1291 (1996).

    PubMed  Google Scholar 

  28. Dougados, M. et al. Sulfasalazine in the treatment of spondylarthropathy. A randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheumatol. 38, 618–627 (1995).

    CAS  Google Scholar 

  29. Clegg, D. O., Reda, D. J. & Abdellatif, M. Comparison of sulfasalazine and placebo for the treatment of axial and peripheral articular manifestations of the seronegative spondylarthropathies: A Department of Veterans Affairs cooperative study. Arthritis Rheumatol. 42, 2325–2329 (1999).

    CAS  Google Scholar 

  30. Nissilä, M. et al. Sulfasalazine in the treatment of ankylosing spondylitis. A twenty-six-week, placebo-controlled clinical trial. Arthritis Rheumatol. 31, 1111–1116 (1988).

    Google Scholar 

  31. Gupta, A. K. et al. Sulfasalazine therapy for psoriatic arthritis: a double blind, placebo controlled trial. J. Rheumatol. 22, 894–898 (1995).

    CAS  PubMed  Google Scholar 

  32. Clegg, D. O. et al. Comparison of sulfasalazine and placebo in the treatment of psoriatic arthritis. A Department of Veterans Affairs Cooperative Study. Arthritis Rheumatol. 39, 2013–2020 (1996).

    CAS  Google Scholar 

  33. Schlienger, R. G., Bircher, A. J. & Meier, C. R. Minocycline-induced lupus. Dermatology 200, 223–231 (2000).

    CAS  PubMed  Google Scholar 

  34. Clementz, G. L. & Dolin, B. J. Sulfasalazine-induced lupus erythematosus. Am. J. Med. 84, 535–538 (1988).

    CAS  PubMed  Google Scholar 

  35. Davidson, A. M. & Birt, A. R. Quinine bisulfate as a desensitizing agent in treatment of lupus erythematosus. Arch. Dermatol. Syphilol. 37, 247–253 (1938).

    CAS  Google Scholar 

  36. Wallace, D. Antimalarials—the ‘real’ advance in lupus. Lupus 10, 385–387 (2001).

    CAS  PubMed  Google Scholar 

  37. Page, F. Treatment of lupus erythematosus with mepacrine. Lancet 258, 755–758 (1951).

    Google Scholar 

  38. Tye, M. J., White, H., Appel, B. & Ansell, H. B. Lupus erythematosus treated with a combination of quinacrine, hydroxychloroquine and chloroquine. N. Engl. J. Med. 260, 63–66 (1959).

    CAS  PubMed  Google Scholar 

  39. Rainsford, K. D., Parke, A. L., Clifford-Rashotte, M. & Kean, W. F. Therapy and pharmacological properties of hydroxychloroquine and chloroquine in treatment of systemic lupus erythematosus, rheumatoid arthritis and related diseases. Inflammopharmacology 23, 231–269 (2015).

    CAS  PubMed  Google Scholar 

  40. Hench, P. S. & Kendall, E. C. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc. Staff Meet. Mayo Clin. 24, 181–197 (1949).

    CAS  PubMed  Google Scholar 

  41. The Nobel Prize. The Nobel Prize in Physiology or Medicine 1950. NobelPrize.org https://www.nobelprize.org/prizes/medicine/1950/summary/ (2019).

  42. Dubois, E. L., Commons, R. R., Starr, P., Stein, C. S. & Morrison, R. Corticotropin and cortisone treatment for systemic lupus erythematosus. J. Am. Med. Assoc. 149, 995–1002 (1952).

    CAS  PubMed  Google Scholar 

  43. Soffer, L. J. Corticotropin and cortisone in acute disseminated lupus erythematosus. J. Am. Med. Assoc. 149, 1002 (2011).

    Google Scholar 

  44. Dordick, J. R. & Gluck, E. J. Preliminary clinical trial with prednisone (meticorten) in systemic lupus erythematosus. AMA Arch. Dermatol. 72, 276–278 (1955).

    CAS  Google Scholar 

  45. Bollet, A. J. Treatment of systemic lupus erythematosus with prednisone and prednisolone. J. Am. Med. Assoc. 159, 1501 (2011).

    Google Scholar 

  46. Hart, F. D. Cortisone and ACTH in treatment of ankylosing spondylitis. Br. Med. J. 1, 188–190 (1952).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Walshe, J. M. Penicillamine, a new oral therapy for Wilson’s disease. Am. J. Med. 21, 487–495 (1956).

    CAS  PubMed  Google Scholar 

  48. Jaffe, I. A. Rheumatoid arthritis with arteritis; report of a case treated with penicillamine. Ann. Intern. Med. 61, 556–563 (1964).

    CAS  PubMed  Google Scholar 

  49. Multicentre Trial Group. Controlled trial of d(-)penicillamine in severe rheumatoid arthritis. Lancet 301, 275–280 (1973).

    Google Scholar 

  50. Jaffe, I. A. Comparison of the effect of plasmapheresis and penicillamine on the level of circulating rheumatoid factor. Ann. Rheum. Dis. 22, 71–76 (1963).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lipsky, P. E. & Ziff, M. Inhibition of human helper T cell function in vitro by D-penicillamine and CuSO4. J. Clin. Invest. 65, 1069–1076 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Steven, M. M., Morrison, M. & Sturrock, R. D. Penicillamine in ankylosing spondylitis: a double blind placebo controlled trial. J. Rheumatol. 12, 735–737 (1985).

    CAS  PubMed  Google Scholar 

  53. Bernacka, K., Tytman, K. & Sierakowski, S. Clinical application of D-penicillamine in ankylosing spondylitis: a 9-month study. Med. Interne 27, 295–301 (1989).

    CAS  PubMed  Google Scholar 

  54. Price, R. & Gibson, T. D-penicillamine and psoriatic arthropathy. Br. J. Rheumatol. 25, 228 (1986).

    CAS  PubMed  Google Scholar 

  55. Dell’era, L., Boati, E., Nebbia, G. & Corona, F. Wilson’s disease treated with penicillamine and lupus erythematosus: related or distinct entities? Minerva Pediatr. 64, 55–57 (2012).

    PubMed  Google Scholar 

  56. Lin, H. C. et al. Penicillamine induced lupus-like syndrome: a case report. J. Microbiol. Immunol. Infect. 33, 202–204 (2000).

    CAS  PubMed  Google Scholar 

  57. Iwatani, M. et al. Efficacy profile of bucillamine in rheumatoid arthritis patients in a large observational cohort study, IORRA. Mod. Rheumatol. 16, 376–380 (2006).

    CAS  PubMed  Google Scholar 

  58. Gubner, R., August, S. & Ginsberg, V. Therapeutic suppression of tissue reactivity. II. Effect of aminopterin in rheumatoid arthritis and psoriasis. Am. J. Med. Sci. 221, 176–182 (1951).

    CAS  PubMed  Google Scholar 

  59. Weinblatt, M. E. et al. Efficacy of low-dose methotrexate in rheumatoid arthritis. N. Engl. J. Med. 312, 818–822 (1985).

    CAS  PubMed  Google Scholar 

  60. Cuellar, M. L. & Espinoza, L. R. Methotrexate use in psoriasis and psoriatic arthritis. Rheum. Dis. Clin. North. Am. 23, 797–809 (1997).

    CAS  PubMed  Google Scholar 

  61. Braun, J. & Sieper, J. Therapy of ankylosing spondylitis and other spondyloarthritides: established medical treatment, anti-TNF-α therapy and other novel approaches. Arthritis Res. 4, 307 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Carneiro, J. R. & Sato, E. I. Double blind, randomized, placebo controlled clinical trial of methotrexate in systemic lupus erythematosus. J. Rheumatol. 26, 1275–1279 (1999).

    CAS  PubMed  Google Scholar 

  63. Fortin, P. R. et al. Steroid-sparing effects of methotrexate in systemic lupus erythematosus: a double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 59, 1796–1804 (2008).

    CAS  Google Scholar 

  64. Drinkard, J. P. et al. Azathioprine and prednisone in the treatment of adults with lupus nephritis. Clinical, histological, and immunological changes with therapy. Medicine 49, 411–432 (1970).

    CAS  PubMed  Google Scholar 

  65. Price, E. J., Rigby, S. P., Clancy, U. & Venables, P. J. A double blind placebo controlled trial of azathioprine in the treatment of primary Sjögren’s syndrome. J. Rheumatol. 25, 896–899 (1998).

    CAS  PubMed  Google Scholar 

  66. Fricke, R. & Petersen, D. Treatment of ankylosing spondylitis with cyclophosphamide and azathioprine [article in German]. Verh. Dtsch. Ges. Rheumatol. 1, 189–195 (1969).

    CAS  PubMed  Google Scholar 

  67. Sadowska-Wróblewska, M., Garwolin´ska, H. & Maczyn´ska-Rusiniak, B. A trial of cyclophosphamide in ankylosing spondylitis with involvement of peripheral joints and high disease activity. Scand. J. Rheumatol. 15, 259–264 (1986).

    PubMed  Google Scholar 

  68. Ginzler, E. M. et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N. Engl. J. Med. 353, 2219–2228 (2005).

    CAS  PubMed  Google Scholar 

  69. Yocum, D. E. et al. Efficacy and safety of tacrolimus in patients with rheumatoid arthritis: a double-blind trial. Arthritis Rheumatol. 48, 3328–3337 (2003).

    CAS  Google Scholar 

  70. Kawai, S. et al. Comparison of tacrolimus and mizoribine in a randomized, double-blind controlled study in patients with rheumatoid arthritis. J. Rheumatol. 33, 2153–2161 (2006).

    CAS  PubMed  Google Scholar 

  71. Dutta, S. & Ahmad, Y. The efficacy and safety of tacrolimus in rheumatoid arthritis. Ther. Adv. Musculoskelet. Dis. 3, 283–291 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Furst, D. E. et al. Efficacy of tacrolimus in rheumatoid arthritis patients who have been treated unsuccessfully with methotrexate: a six-month, double-blind, randomized, dose-ranging study. Arthritis Rheumatol. 46, 2020–2028 (2002).

    CAS  Google Scholar 

  73. Takahashi, S. et al. Efficacy and safety of tacrolimus for induction therapy in patients with active lupus nephritis. Mod. Rheumatol. 21, 282–289 (2011).

    CAS  PubMed  Google Scholar 

  74. Miyasaka, N., Kawai, S. & Hashimoto, H. Efficacy and safety of tacrolimus for lupus nephritis: a placebo-controlled double-blind multicenter study. Mod. Rheumatol. 19, 606–615 (2009).

    CAS  PubMed  Google Scholar 

  75. Lai, Z.-W. et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391, 1186–1196 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Tugwell, P. et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N. Engl. J. Med. 333, 137–142 (1995).

    CAS  PubMed  Google Scholar 

  77. Devecı, H. & Kobak, S. The efficacy of topical 0.05% cyclosporine A in patients with dry eye disease associated with Sjögren’s syndrome. Int. Ophthalmol. 34, 1043–1048 (2014).

    PubMed  Google Scholar 

  78. Sumethkul, K., Kitumnuaypong, T., Angthararak, S. & Pichaiwong, W. Low-dose cyclosporine for active lupus nephritis: a dose titration approach. Clin. Rheumatol. 38, 2151–2159 (2019).

    PubMed  Google Scholar 

  79. Bartlett, R. R. et al. Leflunomide (HWA 486), a novel immunomodulating compound for the treatment of autoimmune disorders and reactions leading to transplantation rejection. Agents Actions 32, 10–21 (1991).

    CAS  PubMed  Google Scholar 

  80. [No authors listed]. Leflunomide approved for rheumatoid arthritis; other drugs nearing approval. Am. J. Health Syst. Pharm. 55, 2225–2226 (1998).

  81. van Woerkom, J. M. et al. Safety and efficacy of leflunomide in primary Sjögren’s syndrome: a phase II pilot study. Ann. Rheum. Dis. 66, 1026–1032 (2007).

    PubMed  PubMed Central  Google Scholar 

  82. van Denderen, J. C. et al. Double blind, randomised, placebo controlled study of leflunomide in the treatment of active ankylosing spondylitis. Ann. Rheum. Dis. 64, 1761–1764 (2005).

    PubMed  PubMed Central  Google Scholar 

  83. Tam, L.-S., Li, E. K., Wong, C.-K., Lam, C. W. & Szeto, C.-C. Double-blind, randomized, placebo-controlled pilot study of leflunomide in systemic lupus erythematosus. Lupus 13, 601–604 (2004).

    CAS  PubMed  Google Scholar 

  84. Remer, C. F., Weisman, M. H. & Wallace, D. J. Benefits of leflunomide in systemic lupus erythematosus: a pilot observational study. Lupus 10, 480–483 (2001).

    CAS  PubMed  Google Scholar 

  85. Wang, H. et al. Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study. Lupus 17, 638–644 (2008).

    CAS  PubMed  Google Scholar 

  86. Zhang, F. S. et al. The efficacy and safety of leflunomide therapy in lupus nephritis by repeat kidney biopsy. Rheumatol. Int. 29, 1331–1335 (2009).

    CAS  PubMed  Google Scholar 

  87. Zhang, M. et al. Leflunomide versus cyclophosphamide in the induction treatment of proliferative lupus nephritis in Chinese patients: a randomized trial. Clin. Rheumatol. 38, 859–867 (2019).

    PubMed  Google Scholar 

  88. Tam, L.-S. et al. Safety and efficacy of leflunomide in the treatment of lupus nephritis refractory or intolerant to traditional immunosuppressive therapy: an open label trial. Ann. Rheum. Dis. 65, 417–418 (2006).

    PubMed  PubMed Central  Google Scholar 

  89. Singh, H. Rare occurrence of drug induced subacute cutaneous lupus erythematosus with leflunomide therapy. J. Clin. Diagn. Res. 10, OD06 - OD07 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. Marzano, A., Ramoni, S., Del Papa, N., Barbareschi, M. & Alessi, E. Leflunomide-induced subacute cutaneous lupus erythematosus with erythema multiforme-like lesions. Lupus 17, 329–331 (2008).

    CAS  PubMed  Google Scholar 

  91. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03866317 (2019).

  92. Sieper, J. et al. 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 (2013).

    CAS  PubMed  Google Scholar 

  93. Burness, C. B. & Deeks, E. D. Adalimumab: in non-radiographic axial spondyloarthritis. Drugs 72, 2385–2395 (2012).

    CAS  PubMed  Google Scholar 

  94. Goodwin, J. S. & Goodwin, J. M. Failure to recognize efficacious treatments: a history of salicylate therapy in rheumatoid arthritis. Perspect. Biol. Med. 25, 78–92 (1981).

    CAS  PubMed  Google Scholar 

  95. Halford, G. M., Lordkipanidzé, M. & Watson, S. P. 50th anniversary of the discovery of ibuprofen: an interview with Dr Stewart Adams. Platelets 23, 415–422 (2012).

    CAS  PubMed  Google Scholar 

  96. Nash, P. & Clegg, D. O. Psoriatic arthritis therapy: NSAIDs and traditional DMARDs. Ann. Rheum. Dis. 64, ii74–ii77 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Østensen, M. & Villiger, P. M. Nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus. Lupus 9, 566–572 (2000).

    PubMed  Google Scholar 

  98. Monaco, C., Nanchahal, J., Taylor, P. & Feldmann, M. Anti-TNF therapy: past, present and future. Int. Immunol. 27, 55–62 (2015).

    CAS  PubMed  Google Scholar 

  99. Davis, J. C. et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: a randomized, controlled trial. Arthritis Rheumatol. 48, 3230–3236 (2003).

    CAS  Google Scholar 

  100. Present, D. H. et al. Infliximab for the treatment of fistulas in patients with Crohn’s disease. N. Engl. J. Med. 340, 1398–1405 (1999).

    CAS  PubMed  Google Scholar 

  101. Sandborn, W. J. et al. Certolizumab pegol for the treatment of Crohn’s disease. N. Engl. J. Med. 357, 228–238 (2007).

    CAS  PubMed  Google Scholar 

  102. Lipsky, P. E. et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. N. Engl. J. Med. 343, 1594–1602 (2000).

    CAS  PubMed  Google Scholar 

  103. Keystone, E. et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 58, 3319–3329 (2008).

    CAS  Google Scholar 

  104. Van Der Heijde, D. et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis: results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheumatol. 52, 582–591 (2005).

    Google Scholar 

  105. van der Heijde, D. et al. Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA. Rheumatology 56, 1498–1509 (2017).

    PubMed  PubMed Central  Google Scholar 

  106. Antoni, C. et al. Infliximab improves signs and symptoms of psoriatic arthritis: results of the IMPACT 2 trial. Ann. Rheum. Dis. 64, 1150–1157 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Mease, P. J. et al. Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA). Ann. Rheum. Dis. 73, 48–55 (2014).

    CAS  PubMed  Google Scholar 

  108. Weinblatt, M. E. et al. Adalimumab, a fully human anti–tumor necrosis factor α monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: The ARMADA trial. Arthritis Rheumatol. 48, 35–45 (2003).

    CAS  Google Scholar 

  109. Smolen, J. S. et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor α inhibitors (GO-AFTER study): a multicentre, randomised, double-blind, placebo-controlled, phase III trial. Lancet 374, 210–221 (2009).

    CAS  PubMed  Google Scholar 

  110. Mease, P. J. et al. Adalimumab for the treatment of patients with moderately to severely active psoriatic arthritis: results of a double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 52, 3279–3289 (2005).

    CAS  Google Scholar 

  111. Kavanaugh, A. et al. Safety and efficacy of intravenous golimumab in patients with active psoriatic arthritis. Arthritis Rheumatol. 69, 2151–2161 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Deodhar, A. et al. 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 (2018).

    CAS  PubMed  Google Scholar 

  113. Revicki, D. A. et al. Adalimumab reduces pain, fatigue, and stiffness in patients with ankylosing spondylitis: results from the adalimumab trial evaluating long-term safety and efficacy for ankylosing spondylitis (ATLAS). J. Rheumatol. 35, 1346–1353 (2008).

    CAS  PubMed  Google Scholar 

  114. Blasco-Morente, G., Notario-Ferreira, I., Rueda-Villafranca, B. & Tercedor-Sánchez, J. Subacute cutaneous lupus erythematosus induced by golimumab. Med. Clin. 145, 226–227 (2015).

    Google Scholar 

  115. Swale, V. J., Perrett, C. M., Denton, C. P., Black, C. M. & Rustin, M. H. A. Etanercept-induced systemic lupus erythematosus. Clin. Exp. Dermatol. 28, 604–607 (2003).

    CAS  PubMed  Google Scholar 

  116. Zhu, L. J., Yang, X. & Yu, X. Q. Anti-TNF-α therapies in systemic lupus erythematosus. J. Biomed. Biotechnol. 2010, 465898 (2010).

    PubMed  PubMed Central  Google Scholar 

  117. Cortés-Hernández, J., Egri, N., Vilardell-Tarrés, M. & Ordi-Ros, J. Etanercept in refractory lupus arthritis: an observational study. Semin. Arthritis Rheumatol. 44, 672–679 (2015).

    Google Scholar 

  118. Goldbach-Mansky, R. Blocking interleukin-1 in rheumatic diseases. Ann. N Y. Acad. Sci. 1182, 111–123 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Fisher, C. J. et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase III rhIL-1ra Sepsis Syndrome Study Group. JAMA 271, 1836–1843 (1994).

    PubMed  Google Scholar 

  120. Bresnihan, B. et al. Treatment of rheumatoid arthritis with recombinant human interleukin-1 receptor antagonist. Arthritis Rheumatol. 41, 2196–2204 (1998).

    CAS  Google Scholar 

  121. Cohen, S. et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 46, 614–624 (2002).

    CAS  Google Scholar 

  122. Norheim, K. B., Harboe, E., Gøransson, L. G. & Omdal, R. Interleukin-1 inhibition and fatigue in primary Sjögren’s syndrome-a double blind, randomised clinical trial. PLOS ONE 7, e30123 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Alten, R. et al. Efficacy and safety of the human anti-IL-1β monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study. BMC Musculoskelet. Disord. 12, 153 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Ait-Oudhia, S., Lowe, P. J. & Mager, D. E. Bridging clinical outcomes of canakinumab treatment in patients with rheumatoid arthritis with a population model of IL-1β kinetics. CPT Pharmacomet. Syst. Pharmacol. 1, e5 (2012).

    CAS  Google Scholar 

  125. Maloney, D. G. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin’s lymphoma. Blood 90, 2188–2195 (1997).

    CAS  PubMed  Google Scholar 

  126. Protheroe, A., Edwards, J. C. W., Simmons, A., Maclennan, K. & Selby, P. Remission of inflammatory arthropathy in association with anti-CD20 therapy for non-Hodgkin’s lymphoma. Rheumatology 38, 1150–1152 (1999).

    CAS  PubMed  Google Scholar 

  127. Leandro, M. J., Edwards, J. C., Cambridge, G., Ehrenstein, M. R. & Isenberg, D. A. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheumatol. 46, 2673–2677 (2002).

    Google Scholar 

  128. Edwards, J. C. W. et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004).

    CAS  PubMed  Google Scholar 

  129. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00299130 (2017).

  130. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00266227 (2013).

  131. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00299104 (2017).

  132. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00137969 (2019).

  133. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00282347 (2015).

  134. Looney, R. J. et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheumatol. 50, 2580–2589 (2004).

    CAS  Google Scholar 

  135. Leandro, M. J., Cambridge, G., Edwards, J. C., Ehrenstein, M. R. & Isenberg, D. A. B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients. Rheumatology 44, 1542–1545 (2005).

    CAS  PubMed  Google Scholar 

  136. Tony, H.-P. et al. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID). Arthritis Res. Ther. 13, R75 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Witt, M. et al. Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE)—results from a nationwide cohort in Germany (GRAID). Lupus 22, 1142–1149 (2013).

    CAS  PubMed  Google Scholar 

  138. Sfikakis, P. P. et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheumatol. 52, 501–513 (2005).

    CAS  Google Scholar 

  139. Clair, E. W. S. et al. Rituximab therapy for primary Sjögren’s syndrome: an open-label clinical trial and mechanistic analysis. Arthritis Rheumatol. 65, 1097 (2013).

    Google Scholar 

  140. Dass, S. et al. Reduction of fatigue in Sjögren syndrome with rituximab: results of a randomised, double-blind, placebo-controlled pilot study. Ann. Rheum. Dis. 67, 1541–1544 (2008).

    CAS  PubMed  Google Scholar 

  141. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00071812 (2013).

  142. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00657007 (2013).

  143. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00071487 (2013).

  144. Stohl, W. et al. Efficacy and safety of belimumab in patients with rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled, dose-ranging study. J. Rheumatol. 40, 579–589 (2013).

    CAS  PubMed  Google Scholar 

  145. Schiff, M. et al. Efficacy and safety of tabalumab, an anti-BAFF monoclonal antibody, in patients with moderate-to-severe rheumatoid arthritis and inadequate response to TNF inhibitors: results of a randomised, double-blind, placebo-controlled, phase 3 study. RMD Open 1, e000037 (2015).

    PubMed  PubMed Central  Google Scholar 

  146. Merrill, J. T. et al. Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 75, 332–340 (2016).

    CAS  PubMed  Google Scholar 

  147. Isenberg, D. A. et al. Efficacy and safety of subcutaneous tabalumab in patients with systemic lupus erythematosus: results from ILLUMINATE-1, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 75, 323–331 (2016).

    CAS  PubMed  Google Scholar 

  148. van Vollenhoven, R. F., Wax, S., Li, Y. & Tak, P. P. Safety and efficacy of atacicept in combination with rituximab for reducing the signs and symptoms of rheumatoid arthritis: a phase II, randomized, double-blind, placebo-controlled pilot trial. Arthritis Rheumatol. 67, 2828–2836 (2015).

    PubMed  PubMed Central  Google Scholar 

  149. Ginzler, E. M. et al. Atacicept in combination with MMF and corticosteroids in lupus nephritis: results of a prematurely terminated trial. Arthritis Res. Ther. 14, R33 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Isenberg, D. et al. Efficacy and safety of atacicept for prevention of flares in patients with moderate-to-severe systemic lupus erythematosus (SLE): 52-week data (APRIL-SLE randomised trial). Ann. Rheum. Dis. 74, 2006–2015 (2015).

    CAS  PubMed  Google Scholar 

  151. Merrill, J. T. et al. Phase III trial results with blisibimod, a selective inhibitor of B-cell activating factor, in subjects with systemic lupus erythematosus (SLE): results from a randomised, double-blind, placebo-controlled trial. Ann. Rheum. Dis. 77, 883–889 (2018).

    CAS  PubMed  Google Scholar 

  152. Merrill, J. T. et al. The efficacy and safety of abatacept in patients with non-life-threatening manifestations of systemic lupus erythematosus: results of a twelve-month, multicenter, exploratory, phase IIb, randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 62, 3077–3087 (2010).

    CAS  Google Scholar 

  153. Song, I.-H. et al. Treatment of active ankylosing spondylitis with abatacept: an open-label, 24-week pilot study. Ann. Rheum. Dis. 70, 1108–1110 (2011).

    CAS  PubMed  Google Scholar 

  154. Lekpa, F. K. et al. Lack of efficacy of abatacept in axial spondylarthropathies refractory to tumor-necrosis-factor inhibition. Joint Bone Spine 79, 47–50 (2012).

    CAS  PubMed  Google Scholar 

  155. Meiners, P. M. et al. Abatacept treatment reduces disease activity in early primary Sjögren’s syndrome (open-label proof of concept ASAP study). Ann. Rheum. Dis. 73, 1393–1396 (2014).

    CAS  PubMed  Google Scholar 

  156. Mease, P. J. et al. Efficacy and safety of abatacept, a T-cell modulator, in a randomised, double-blind, placebo-controlled, phase III study in psoriatic arthritis. Ann. Rheum. Dis. 76, 1550–1558 (2017).

    CAS  PubMed  Google Scholar 

  157. Ding, C. & Jones, G. Anti-interleukin-6 receptor antibody treatment in inflammatory autoimmune diseases. Rev. Recent. Clin. Trials 1, 193–200 (2006).

    CAS  PubMed  Google Scholar 

  158. Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheumatol. 62, 542–552 (2010).

    CAS  Google Scholar 

  159. Rovin, B. H. & Parikh, S. V. Lupus nephritis: the evolving role of novel therapeutics. Am. J. Kidney Dis. 63, 677–690 (2014).

    PubMed  PubMed Central  Google Scholar 

  160. Wallace, D. J. et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial. Ann. Rheum. Dis. 76, 534–542 (2017).

    CAS  PubMed  Google Scholar 

  161. Sieper, J. et al. Sarilumab for the treatment of ankylosing spondylitis: results of a Phase II, randomised, double-blind, placebo-controlled study (ALIGN). Ann. Rheum. Dis. 74, 1051–1057 (2015).

    CAS  PubMed  Google Scholar 

  162. Sieper, J., Porter-Brown, B., Thompson, L., Harari, O. & Dougados, M. Assessment of short-term symptomatic efficacy of tocilizumab in ankylosing spondylitis: results of randomised, placebo-controlled trials. Ann. Rheum. Dis. 73, 95–100 (2014).

    CAS  PubMed  Google Scholar 

  163. Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).

    CAS  PubMed  Google Scholar 

  164. Gabay, C. et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 381, 1541–1550 (2013).

    CAS  PubMed  Google Scholar 

  165. Mease, P. J. et al. The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis. Arthritis Rheumatol. 68, 2163–2173 (2016).

    CAS  PubMed  Google Scholar 

  166. Smolen, J. S. et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis despite treatment with methotrexate. Ann. Rheum. Dis. 76, 831–839 (2017).

    CAS  PubMed  Google Scholar 

  167. Poddubnyy, D., Hermann, K.-G. A., Callhoff, J., Listing, J. & Sieper, J. Ustekinumab for the treatment of patients with active ankylosing spondylitis: results of a 28-week, prospective, open-label, proof-of-concept study (TOPAS). Ann. Rheum. Dis. 73, 817–823 (2014).

    CAS  PubMed  Google Scholar 

  168. van Vollenhoven, R. F. et al. Efficacy and safety of ustekinumab, an IL-12 and IL-23 inhibitor, in patients with active systemic lupus erythematosus: results of a multicentre, double-blind, phase 2, randomised, controlled study. Lancet 392, 1330–1339 (2018).

    PubMed  Google Scholar 

  169. Hueber, W. et al. Effects of AIN457, a fully human antibody to interleukin-17A, on psoriasis, rheumatoid arthritis, and uveitis. Sci. Transl. Med. 2, 52ra72–52ra72 (2010).

    PubMed  Google Scholar 

  170. Langley, R. G. et al. Secukinumab in plaque psoriasis—results of two phase 3 trials. N. Engl. J. Med. 371, 326–338 (2014).

    PubMed  Google Scholar 

  171. Baeten, D. et al. Secukinumab, an interleukin-17A inhibitor, in ankylosing spondylitis. N. Engl. J. Med. 373, 2534–2548 (2015).

    CAS  PubMed  Google Scholar 

  172. Grammer, A. et al. Drug repositioning in SLE: crowd-sourcing, literature-mining and Big Data analysis. Lupus 25, 1150–1170 (2016).

    CAS  PubMed  Google Scholar 

  173. Grammer, A. C., Ryals, M. M., Catalina, M. D. & Lipsky, P. E. Repositioning drugs for systemic lupus erythematosus. in Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects 567–575 (Academic Press, 2016).

  174. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03517722 (2019).

  175. Leonardi, C. L. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Lancet 371, 1665–1674 (2008).

    CAS  PubMed  Google Scholar 

  176. Cingoz, O. Ustekinumab. MAbs 1, 216–221 (2009).

    PubMed  PubMed Central  Google Scholar 

  177. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02407223 (2019).

  178. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03159936 (2019).

  179. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03502616 (2019).

  180. Wallace, D. J. et al. Baricitinib for systemic lupus erythematosus: a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet 392, 222–231 (2018).

    CAS  PubMed  Google Scholar 

  181. Kavanaugh, A. et al. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J. Rheumatol. 42, 479–488 (2015).

    CAS  PubMed  Google Scholar 

  182. Cutolo, M. et al. A phase III, randomized, controlled trial of apremilast in patients with psoriatic arthritis: results of the PALACE 2 trial. J. Rheumatol. 43, 1724–1734 (2016).

    PubMed  Google Scholar 

  183. Edwards, C. J. et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with psoriatic arthritis and current skin involvement: a phase III, randomised, controlled trial (PALACE 3). Ann. Rheum. Dis. 75, 1065–1073 (2016).

    CAS  PubMed  Google Scholar 

  184. Genovese, M. C. et al. Apremilast in patients with active rheumatoid arthritis: a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 67, 1703–1710 (2015).

    CAS  PubMed  Google Scholar 

  185. De Souza, A., Strober, B. E., Merola, J. F., Oliver, S. & Franks, A. G. Apremilast for discoid lupus erythematosus: results of a phase 2, open-label, single-arm, pilot study. J. Drugs Dermatol. 11, 1224–1226 (2012).

    PubMed  Google Scholar 

  186. Celgene. Celgene Reports Results from the Phase III POSTURE Study Evaluating Oral OTEZLA® in Ankylosing Spondylitis. https://ir.celgene.com/press-releases/press-release-details/2014/Celgene-Reports-Results-from-the-Phase-III-POSTURE-Study-Evaluating-Oral-OTEZLA-in-Ankylosing-Spondylitis/default.aspx (2014).

  187. Xu, R. & Wang, Q. A genomics-based systems approach towards drug repositioning for rheumatoid arthritis. BMC Genom. 17, 518 (2016).

    Google Scholar 

  188. Labonte, A. C. et al. Identification of alterations in macrophage activation associated with disease activity in systemic lupus erythematosus. PLOS ONE 13, e0208132 (2018).

    PubMed  PubMed Central  Google Scholar 

  189. Kingsmore, K. M., Lipsky, P. E. & Grammer, A. C. R. in Systemic Lupus Erythematosus: Basic, Applied and Clinical Aspects (ed. Tsokos G. C.) (Elsevier 2016).

  190. Kegerreis, B. et al. Machine learning approaches to predict lupus disease activity from gene expression data. Sci. Rep. 9, 9617 (2019).

    PubMed  PubMed Central  Google Scholar 

  191. Gilson, M. K. et al. BindingDB in 2015: a public database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Res. 44, D1045–D1053 (2016).

    CAS  PubMed  Google Scholar 

  192. Wang, X. et al. PharmMapper 2017 update: a web server for potential drug target identification with a comprehensive target pharmacophore database. Nucleic Acids Res. 45, W356–W360 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. Janes, J. et al. The ReFRAME library as a comprehensive drug repurposing library and its application to the treatment of cryptosporidiosis. Proc. Natl Acad. Sci. USA 115, 10750–10755 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  194. Wu, Z. et al. SDTNBI: an integrated network and chemoinformatics tool for systematic prediction of drug–target interactions and drug repositioning. Brief. Bioinform. 18, bbw012 (2016).

    Google Scholar 

  195. Kuhn, M., von Mering, C., Campillos, M., Jensen, L. J. & Bork, P. STITCH: interaction networks of chemicals and proteins. Nucleic Acids Res. 36, D684–D688 (2008).

    CAS  PubMed  Google Scholar 

  196. Szklarczyk, D. et al. STITCH 5: augmenting protein–chemical interaction networks with tissue and affinity data. Nucleic Acids Res. 44, D380–D384 (2016).

    CAS  PubMed  Google Scholar 

  197. Sun, J., Wu, Y., Xu, H. & Zhao, Z. DTome: a web-based tool for drug-target interactome construction. BMC Bioinform. 13, S7 (2012).

    Google Scholar 

  198. Matsoukas, M.-T. et al. Identification of small-molecule inhibitors of calcineurin-NFATc signaling that mimic the PxIxIT motif of calcineurin binding partners. Sci. Signal. 8, ra63–ra63 (2015).

    PubMed  Google Scholar 

  199. Rodrigues-Vendramini, F. A. V. et al. Promising new antifungal treatment targeting chorismate synthase from Paracoccidioides brasiliensis. Antimicrob. Agents Chemother. 63, e01097–18 (2019).

    Google Scholar 

  200. Latek, D., Rutkowska, E., Niewieczerzal, S. & Cielecka-Piontek, J. Drug-induced diabetes type 2: in silico study involving class B GPCRs. PLOS ONE 14, e0208892 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  201. Kumar, S. et al. Computational approaches: discovery of GTPase HRas as prospective drug target for 1,3-diazine scaffolds. BMC Chem. 13, 96 (2019).

    PubMed  PubMed Central  Google Scholar 

  202. Li, H. et al. In silico investigation of the pharmacological mechanisms of beneficial effects of Ginkgo biloba L. on Alzheimer’s disease. Nutrients 10, E589 (2018).

    Google Scholar 

  203. Carrella, D. et al. Mantra 2.0: an online collaborative resource for drug mode of action and repurposing by network analysis. Bioinformatics 30, 1787–1788 (2014).

    CAS  PubMed  Google Scholar 

  204. Napolitano, F., Sirci, F., Carrella, D. & di Bernardo, D. Drug-set enrichment analysis: a novel tool to investigate drug mode of action. Bioinformatics 32, 235 (2016).

    CAS  PubMed  Google Scholar 

  205. de Anda-Jáuregui, G., Guo, K., McGregor, B. A. & Hur, J. Exploration of the anti-inflammatory drug space through network pharmacology: applications for drug repurposing. Front. Physiol. 9, 151 (2018).

    PubMed  PubMed Central  Google Scholar 

  206. Brown, A. S. & Patel, C. J. MeSHDD: literature-based drug-drug similarity for drug repositioning. J. Am. Med. Inf. Assoc. 24, 614–618 (2017).

    Google Scholar 

  207. Campillos, M., Kuhn, M., Gavin, A. C., Jensen, L. J. & Bork, P. Drug target identification using side-effect similarity. Science 321, 263–266 (2008).

    CAS  PubMed  Google Scholar 

  208. Kuhn, M., Letunic, I., Jensen, L. J. & Bork, P. The SIDER database of drugs and side effects. Nucleic Acids Res. 44, D1075–D1079 (2016).

    CAS  PubMed  Google Scholar 

  209. Cai, M. C. et al. ADReCS: an ontology database for aiding standardization and hierarchical classification of adverse drug reaction terms. Nucleic Acids Res. 43, D907–D913 (2015).

    CAS  PubMed  Google Scholar 

  210. Huang, L.-H. et al. ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 46, D911–D917 (2018).

    CAS  PubMed  Google Scholar 

  211. Dimitri, G. M. & Lió, P. DrugClust: a machine learning approach for drugs side effects prediction. Comput. Biol. Chem. 68, 204–210 (2017).

    CAS  PubMed  Google Scholar 

  212. Liu, M. et al. Large-scale prediction of adverse drug reactions using chemical, biological, and phenotypic properties of drugs. J. Am. Med. Inf. Assoc. 19, e28–e35 (2012).

    Google Scholar 

  213. Pauwels, E., Stoven, V. & Yamanishi, Y. Predicting drug side-effect profiles: a chemical fragment-based approach. BMC Bioinform. 12, 169 (2011).

    Google Scholar 

  214. Mizutani, S., Pauwels, E., Stoven, V., Goto, S. & Yamanishi, Y. Relating drug–protein interaction network with drug side effects. Bioinformatics 28, i522–i528 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Bresso, E. et al. Integrative relational machine-learning for understanding drug side-effect profiles. BMC Bioinform. 14, 207 (2013).

    Google Scholar 

  216. Poleksic, A. & Xie, L. Predicting serious rare adverse reactions of novel chemicals. Bioinformatics 34, 2835–2842 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  217. Zappacosta, A. R. Reversal of baldness in patient receiving minoxidil for hypertension. N. Engl. J. Med. 303, 1480–1481 (1980).

    CAS  PubMed  Google Scholar 

  218. Wang, K., Wan, M., Wang, R.-S. & Weng, Z. Opportunities for web-based drug repositioning: searching for potential antihypertensive agents with hypotension adverse events. J. Med. Internet Res. 18, e76 (2016).

    PubMed  PubMed Central  Google Scholar 

  219. Kvancz, D. A., Sredzinski, M. N. & Tadlock, C. G. Predictive analytics: a case study in machine-learning and claims databases. Am. J. Pharm. Benefits 8, 214–219 (2016).

    Google Scholar 

  220. Doss, J., Mo, H., Carroll, R. J., Crofford, L. J. & Denny, J. C. Phenome-wide association study of rheumatoid arthritis subgroups identifies association between seronegative disease and fibromyalgia. Arthritis Rheumatol. 69, 291–300 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  221. Gottesman, O. et al. The Electronic Medical Records and Genomics (eMERGE) Network: past, present, and future. Genet. Med. 15, 761–771 (2013).

    PubMed  PubMed Central  Google Scholar 

  222. [No author listed] Sphinx: a resource of the eMERGE Network. https://www.emergesphinx.org (2019).

  223. Denny, J. C. et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat. Biotechnol. 31, 1102–1110 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. International Genetics of Ankylosing Spondylitis Consortium (IGAS) et al. Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci. Nat. Genet. 45, 730–738 (2013).

    Google Scholar 

  225. Bowes, J. et al. Dense genotyping of immune-related susceptibility loci reveals new insights into the genetics of psoriatic arthritis. Nat. Commun. 6, 6046 (2015).

    CAS  PubMed  Google Scholar 

  226. Lessard, C. J. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome. Nat. Genet. 45, 1284–1292 (2013).

    CAS  PubMed  Google Scholar 

  227. Li, Y. et al. A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjögren’s syndrome at 7q11.23. Nat. Genet. 45, 1361–1365 (2013).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  229. Bentham, J. et al. Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus. Nat. Genet. 47, 1457–1464 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  230. Eyre, S., Orozco, G. & Worthington, J. The genetics revolution in rheumatology: large scale genomic arrays and genetic mapping. Nat. Rev. Rheumatol. 13, 421–432 (2017).

    CAS  PubMed  Google Scholar 

  231. Langefeld, C. D. et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat. Commun. 8, 16021 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Sun, C. et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat. Genet. 48, 323–330 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Jarvinen, T. M. et al. Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population. Rheumatology 51, 87–92 (2012).

    PubMed  Google Scholar 

  234. Taylor, P. C. Clinical efficacy of launched JAK inhibitors in rheumatoid arthritis. Rheumatology 58 (Suppl. 1), i17–i26 (2019).

    PubMed  Google Scholar 

  235. Brown, M. A., Kenna, T. & Wordsworth, B. P. Genetics of ankylosing spondylitis—insights into pathogenesis. Nat. Rev. Rheumatol. 12, 81–91 (2016).

    CAS  PubMed  Google Scholar 

  236. Morris, D. L. et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat. Genet. 48, 940–946 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  237. Burton, P. et al. Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat. Genet. 39, 1329–1337 (2007).

    CAS  PubMed  Google Scholar 

  238. Pritchard, J.-L. E., O’Mara, T. A. & Glubb, D. M. Enhancing the promise of drug repositioning through genetics. Front. Pharmacol. 8, 896 (2017).

    PubMed  PubMed Central  Google Scholar 

  239. Moosavinasab, S. et al. ‘RE:fine drugs’: an interactive dashboard to access drug repurposing opportunities. Database 2016, baw083 (2016).

    PubMed  PubMed Central  Google Scholar 

  240. Martin, P. et al. Chromatin interactions reveal novel gene targets for drug repositioning in rheumatic diseases. Ann. Rheum. Dis. 78, 1127–1134 (2019).

    PubMed  Google Scholar 

  241. Fang, H. et al. A genetics-led approach defines the drug target landscape of 30 immune-related traits. Nat. Genet. 51, 1082–1091 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  242. Lamb, J. et al. The connectivity map: using gene-expression signatures to connect small molecules, genes, and disease. Science 313, 1929–1935 (2006).

    CAS  PubMed  Google Scholar 

  243. Subramanian, A. et al. A next generation connectivity map: L1000 platform and the first 1,000,000 profiles. Cell 171, 1437–1452.e17 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  244. Jia, Z. et al. Cogena, a novel tool for co-expressed gene-set enrichment analysis, applied to drug repositioning and drug mode of action discovery. BMC Genomics 17, 414 (2016).

    PubMed  PubMed Central  Google Scholar 

  245. Chen, Y., Li, Y., Narayan, R., Subramanian, A. & Xie, X. Gene expression inference with deep learning. Bioinformatics 32, 1832–1839 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  246. Xie, L., He, S., Song, X., Bo, X. & Zhang, Z. Deep learning-based transcriptome data classification for drug-target interaction prediction. BMC Genomics 19, 667 (2018).

    PubMed  PubMed Central  Google Scholar 

  247. Ganter, B. et al. Development of a large-scale chemogenomics database to improve drug candidate selection and to understand mechanisms of chemical toxicity and action. J. Biotechnol. 119, 219–244 (2005).

    CAS  PubMed  Google Scholar 

  248. Ganter, B., Snyder, R. D., Halbert, D. N. & Lee, M. D. Toxicogenomics in drug discovery and development: mechanistic analysis of compound/class-dependent effects using the DrugMatrix® database. Pharmacogenomics 7, 1025–1044 (2006).

    CAS  PubMed  Google Scholar 

  249. Duan, Q. et al. L1000CDS2: LINCS L1000 characteristic direction signatures search engine. NPJ Syst. Biol. Appl. 2, 16015 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  250. O’Reilly, P. G. et al. QUADrATiC: scalable gene expression connectivity mapping for repurposing FDA-approved therapeutics. BMC Bioinform. 17, 198 (2016).

    Google Scholar 

  251. Grammer, A. C. & Lipsky, P. E. Drug repositioning strategies for the identification of novel therapies for rheumatic autoimmune inflammatory diseases. Rheum. Dis. Clin. N. Am. 43, 467–480 (2017).

    Google Scholar 

  252. Huang, R. et al. The NCGC pharmaceutical collection: a comprehensive resource of clinically approved drugs enabling repurposing and chemical genomics. Sci. Transl. Med. 3, 80ps16 (2011).

    PubMed  PubMed Central  Google Scholar 

  253. Corsello, S. M. et al. The Drug Repurposing Hub: a next-generation drug library and information resource. Nat. Med. 23, 405–408 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  254. Wei, W.-Q. et al. Development and evaluation of an ensemble resource linking medications to their indications. J. Am. Med. Inf. Assoc. 20, 954–961 (2013).

    Google Scholar 

  255. Brown, A. S. & Patel, C. J. A standard database for drug repositioning. Sci. Data 4, 170029 (2017).

    PubMed  PubMed Central  Google Scholar 

  256. Conte, F. et al. A paradigm shift in medicine: a comprehensive review of network-based approaches. Biochim. Biophys. Acta Gene Regul. Mech. 194416 https://doi.org/10.1016/j.bbagrm.2019.194416 (2019).

  257. Vamathevan, J. et al. Applications of machine learning in drug discovery and development. Nat. Rev. Drug. Discov. 18, 463–477 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Ekins, S. et al. Exploiting machine learning for end-to-end drug discovery and development. Nat. Mater. 18, 435–441 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  259. Gottlieb, A., Stein, G. Y., Ruppin, E. & Sharan, R. PREDICT: a method for inferring novel drug indications with application to personalized medicine. Mol. Syst. Biol. 7, 496 (2011).

    PubMed  PubMed Central  Google Scholar 

  260. Barabási, A.-L., Gulbahce, N. & Loscalzo, J. Network medicine: a network-based approach to human disease. Nat. Rev. Genet. 12, 56–68 (2011).

    PubMed  PubMed Central  Google Scholar 

  261. Zeng, X. et al. deepDR: a network-based deep learning approach to in silico drug repositioning. Bioinformatics https://doi.org/10.1093/bioinformatics/btz418 (2019).

  262. Guney, E., Menche, J., Vidal, M. & Barábasi, A.-L. Network-based in silico drug efficacy screening. Nat. Commun. 7, 10331 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  263. Guney, E. Reproducible drug repurposing: when similarity does not suffice. Pac. Symp. Biocomput. 22, 132–143 (2017).

    PubMed  Google Scholar 

  264. Iskar, M. et al. Characterization of drug-induced transcriptional modules: towards drug repositioning and functional understanding. Mol. Syst. Biol. 9, 662 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Stohl, W. et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week randomized, double-blind, placebo-controlled study. Arthritis Rheumatol. 69, 1016–1027 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  266. Anjorin, A. & Lipsky, P. Engaging African ancestry participants in SLE clinical trials. Lupus Sci. Med. 5, 297 (2018).

    Google Scholar 

  267. Dörner, T. & Lipsky, P. E. Beyond pan-B-cell-directed therapy-new avenues and insights into the pathogenesis of SLE. Nat. Rev. Rheumatol. 12, 645–657 (2016).

    PubMed  Google Scholar 

  268. Schamberg, J. F. & Wright, C. S. The use of gold and sodium thiosulphate in the treatment of lupus erythematosus. Arch. Derm. Syphilol. 15, 119–137 (1927).

  269. Alderson, H. E. & Way, S. C. Unusual reaction from gold and sodium thiosulphate injection in treatment of lupus erythematosus. Cal. West. Med. 28, 809 (1928).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Monash, S. & Traub, E. F. Modification of therapy with gold compounds in lupus erythematosus. Arch. Derm. Syphilol. 24, 110 (1931).

  271. Finkelstein, A. E. et al. Auranofin. New oral gold compound for treatment of rheumatoid arthritis. Ann. Rheum. Dis. 35, 251–257 (1976).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Wanders, A. et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheumatol. 52, 1756–1765 (2005).

    CAS  Google Scholar 

  273. Sinclair, R. J. G. & Duthie, J. J. R. Salazopyrin in the treatment of rheumatoid arthritis. Ann. Rheum. Dis. 8, 226–231 (2008).

    Google Scholar 

  274. Kuzell, W. & Gardner, G. Salicylazosulfapyridine (salazopyrin or azopyrin) in rheumatoid arthritis and experimental polyarthritis. Calif. Med. 73, 476–480 (1950).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. McConkey, B. et al. Salazopyrin in rheumatoid arthritis. Agents Actions 8, 438–441 (1978).

    CAS  PubMed  Google Scholar 

  276. McConkey, B. et al. Sulphasalazine in rheumatoid arthritis. Br. Med. J. 280, 442–444 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  277. Skinner, M., Cathcart, E. S., Mills, J. A. & Pinals, R. S. Tetracycline in the treatment of rheumatoid arthritis. A double blind controlled study. Arthritis Rheumatol. 14, 727–732 (1971).

    CAS  Google Scholar 

  278. Pullar, T., Hunter, J. A. & Capell, H. A. Sulphasalazine in rheumatoid arthritis: a double blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br. Med. J. 287, 1102–1104 (1983).

    CAS  Google Scholar 

  279. Shippey, E. A., Wagler, V. D. & Collamer, A. N. Hydroxychloroquine: an old drug with new relevance. Cleve. Clin. J. Med. 85, 459–467 (2018).

    PubMed  Google Scholar 

  280. Bansback, N. et al. Triple therapy versus biologic therapy for active rheumatoid arthritis. Ann. Intern. Med. 167, 8 (2017).

    PubMed  Google Scholar 

  281. Balak, D. & Hajdarbegovic, E. Drug-induced psoriasis: clinical perspectives. Psoriasis Targets Ther. 7, 87–94 (2017).

    CAS  Google Scholar 

  282. Jaffe, I. A. Penicillamine: an anti-rheumatoid drug. Am. J. Med. 75, 63–68 (1983).

    CAS  PubMed  Google Scholar 

  283. Moens, C. Rheumatoid arthritis treated by administration of imuran and actinomycin-c [article in multiple languages]. Arch. Interam. Rheumatol. 8, 278–287 (1965).

    CAS  PubMed  Google Scholar 

  284. Moens, C. & Brocteur, J. Treatment of rheumatoid arthritis with immunosuppressive drugs. I. Clinical study. Acta Rheumatol. Scand. 11, 212–220 (1965).

    CAS  PubMed  Google Scholar 

  285. Black, R. L. et al. Methotrexate therapy in psoriatic arthritis. JAMA 189, 743–747 (1964).

    CAS  PubMed  Google Scholar 

  286. Lorenzen, I. & Videbaek, A. Treatment of collagen diseases with cytostatics. Lancet 2, 558–561 (1965).

    CAS  PubMed  Google Scholar 

  287. Swannell, A. J. & Coomes, E. N. Preliminary results of azathioprine treatment in severe rheumatic disease. Ann. Phys. Med. 10, 112–120 (1969).

    CAS  PubMed  Google Scholar 

  288. Adams, D. A., Gordon, A. & Maxwell, M. H. Azathioprine treatment of immunological renal disease. JAMA 199, 459–463 (1967).

    CAS  PubMed  Google Scholar 

  289. Miescher, P. A. & Riethmueller, D. Diagnosis and treatment of systemic lupus erythematosus. Semin. Hematol. 2, 1–28 (1965).

    CAS  PubMed  Google Scholar 

  290. Sztejnbok, M., Stewart, A., Diamond, H. & Kaplan, D. Azathioprine in the treatment of systemic lupus erythematosus. A controlled study. Arthritis Rheumatol. 14, 639–645 (1971).

    CAS  Google Scholar 

  291. Shah, V. V., Lin, E. J., Reddy, S. P. & Wu, J. J. Methotrexate. in Therapy for Severe Psoriasis 37–48 (Elsevier, 2016).

  292. Gordon, D. A. & Urowitz, M. B. Use of azathioprine for rheumatoid arthritis. Arthritis Rheumatol. 25, 1269–1270 (1982).

    CAS  Google Scholar 

  293. Austin, H. A. et al. Therapy of lupus nephritis. N. Engl. J. Med. 314, 614–619 (1986).

    PubMed  Google Scholar 

  294. Felson, D. T. & Anderson, J. Evidence for the superiority of immunosuppressive drugs and prednisone over prednisone alone in lupus nephritis. N. Engl. J. Med. 311, 1528–1533 (1984).

    CAS  PubMed  Google Scholar 

  295. Willkens, R. F. Methotrexate treatment of rheumatoid arthritis. Ann. Intern. Med. 103, 612 (1985).

    CAS  PubMed  Google Scholar 

  296. Weinblatt, M. E. Methotrexate: who would have predicted its importance in rheumatoid arthritis? Arthritis Res. Ther. 20, 103 (2018).

    PubMed  PubMed Central  Google Scholar 

  297. Gansauge, S., Breitbart, A., Rinaldi, N. & Schwarz-Eywill, M. Methotrexate in patients with moderate systemic lupus erythematosus (exclusion of renal and central nervous system disease). Ann. Rheum. Dis. 56, 382–385 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  298. Kingsley, G. H. et al. A randomized placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology 51, 1368–1377 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  299. Singh, A. K. & Narsipur, S. S. Cyclosporine: a commentary on brand versus generic formulation exchange. J. Transpl. 2011, 1–6 (2011).

    Google Scholar 

  300. Dooley, M. A. et al. Mycophenolate mofetil therapy in lupus nephritis: clinical observations. J. Am. Soc. Nephrol. 10, 833–839 (1999).

    CAS  PubMed  Google Scholar 

  301. Chan, T. M. et al. Efficacy of mycophenolate mofetil in patients with diffuse proliferative lupus nephritis. N. Engl. J. Med. 343, 1156–1162 (2000).

    CAS  PubMed  Google Scholar 

  302. Contreras, G. et al. Sequential therapies for proliferative lupus nephritis. N. Engl. J. Med. 350, 971–980 (2004).

    CAS  PubMed  Google Scholar 

  303. Contreras, G., Tozman, E., Nahar, N. & Metz, D. Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide. Lupus 14, s33–s38 (2005).

    CAS  PubMed  Google Scholar 

  304. Dooley, M. A. et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N. Engl. J. Med. 365, 1886–1895 (2011).

    CAS  PubMed  Google Scholar 

  305. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03865888 (2019).

  306. Asiri, A., Thavaneswaran, A., Kalman-Lamb, G., Chandran, V. & Gladman, D. D. The effectiveness of leflunomide in psoriatic arthritis. Clin. Exp. Rheumatol. 32, 728–731 (2014).

    PubMed  Google Scholar 

  307. van der Heijde, D. et al. Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis. Ann. Rheum. Dis. 67, 1218–1221 (2007).

    PubMed  Google Scholar 

  308. Mease, P. et al. Effect of certolizumab pegol over 96 weeks in patients with psoriatic arthritis with and without prior antitumour necrosis factor exposure. RMD Open 1, e000119 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  309. Fleischmann, R. M. et al. Anakinra, a recombinant human interleukin-1 receptor antagonist (r-metHuIL-1ra), in patients with rheumatoid arthritis: a large, international, multicenter, placebo-controlled trial. Arthritis Rheumatol. 48, 927–934 (2003).

    CAS  Google Scholar 

  310. Kremer, J. M. et al. Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial. Ann. Intern. Med. 144, 865–876 (2006).

    CAS  PubMed  Google Scholar 

  311. Merrill, J. T. et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheumatol. 62, 222–233 (2010).

    CAS  Google Scholar 

  312. Rovin, B. H. et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the lupus nephritis assessment with rituximab study. Arthritis Rheumatol. 64, 1215–1226 (2012).

    CAS  Google Scholar 

  313. AlDhaheri, F. et al. Rituximab can induce remission in a patient with ankylosing spondylitis who failed anti-TNF-α agent. Am. J. Case Rep. 18, 143–147 (2017).

    PubMed  PubMed Central  Google Scholar 

  314. Merrill, J. T. et al. Efficacy and safety of atacicept in patients with systemic lupus erythematosus. Arthritis Rheumatol. 70, 266–276 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  315. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03312907 (2019).

  316. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02631538 (2019).

  317. [No authors listed] Atlizumab: anti-IL-6 receptor antibody – Chugai, anti-interleukin-6 receptor antibody – Chugai, MRA – Chugai. BioDrugs 17, 369–372 (2003).

  318. Rovin, B. H. et al. A multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of treatment with sirukumab (CNTO 136) in patients with active lupus nephritis. Arthritis Rheumatol. 68, 2174–2183 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  319. McKee, S. Ablynx’ vobarilizumab fails in lupus trial. PharmaTimes http://www.pharmatimes.com/news/ablynx_vobarilizumab_fails_in_lupus_trial_1229404 (2018).

  320. Kauffman, C. L. et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J. Invest. Dermatol. 123, 1037–1044 (2004).

    CAS  PubMed  Google Scholar 

  321. Krueger, G. G. et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N. Engl. J. Med. 356, 580–592 (2007).

    CAS  PubMed  Google Scholar 

  322. Papp, K. A. et al. Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Lancet 371, 1675–1684 (2008).

    CAS  PubMed  Google Scholar 

  323. McInnes, I. B. et al. Efficacy and safety of ustekinumab in patients with active psoriatic arthritis: 1 year results of the phase 3, multicentre, double-blind, placebo-controlled PSUMMIT 1 trial. Lancet 382, 780–789 (2013).

    CAS  PubMed  Google Scholar 

  324. Papp, K. A. et al. Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. N Engl. J. Med. 366, 1181–1189 (2012).

    CAS  PubMed  Google Scholar 

  325. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT01059448 (2015).

  326. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT02429882 (2015).

  327. Mease, P. J. et al. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann. Rheum. Dis. 76, 79–87 (2017).

    CAS  PubMed  Google Scholar 

  328. Lebwohl, M. et al. Phase 3 studies comparing brodalumab with ustekinumab in psoriasis. N. Engl. J. Med. 373, 1318–1328 (2015).

    CAS  PubMed  Google Scholar 

  329. van der Heijde, D. et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet 392, 2441–2451 (2018).

    PubMed  Google Scholar 

  330. Deodhar, A. et al. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondyloarthritis: sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheumatol. 71, 599–611 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  331. Janssen. Janssen Submits Application to U.S. FDA Seeking First-in-Class Approval of TREMFYA® (guselkumab) for Treatment of Adults with Active Psoriatic Arthritis. Janssen.com https://www.janssen.com/janssen-submits-application-us-fda-seeking-first-class-approval-tremfya-guselkumab-treatment-adults (2019).

  332. West, K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr. Opin. Investig. Drugs 10, 491–504 (2009).

    CAS  PubMed  Google Scholar 

  333. Schett, G., Sloan, V. S., Stevens, R. M. & Schafer, P. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther. Adv. Musculoskelet. Dis. 2, 271–278 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  334. Burmester, G. R. et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet 381, 451–460 (2013).

    CAS  PubMed  Google Scholar 

  335. Mease, P. et al. Tofacitinib or adalimumab versus placebo for psoriatic arthritis. N. Engl. J. Med. 377, 1537–1550 (2017).

    CAS  PubMed  Google Scholar 

  336. Genovese, M. C. et al. Baricitinib in patients with refractory rheumatoid arthritis. N. Engl. J. Med. 374, 1243–1252 (2016).

    CAS  PubMed  Google Scholar 

  337. US National Library of Medicine. ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT03843125 (2019).

  338. Smolen, J. S. et al. Upadacitinib as monotherapy in patients with active rheumatoid arthritis and inadequate response to methotrexate (SELECT-MONOTHERAPY): a randomised, placebo-controlled, double-blind phase 3 study. Lancet 393, 2303–2311 (2019).

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. AMPEL BioSolutions and RILITE Research Institute, Charlottesville, VA, USA

    Kathryn M. Kingsmore, Amrie C. Grammer & Peter E. Lipsky

Authors
  1. Kathryn M. Kingsmore
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amrie C. Grammer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Peter E. Lipsky
    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 Peter E. Lipsky.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information

Nature Reviews Rheumatology thanks G. Orozco, E. Guney 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.

Supplementary Information

Glossary

In silico

A type of biological thought experiment performed on a computer or using specific computer simulation.

Machine learning

An algorithm by which a computer makes predictions based upon learned patterns in the data.

Pharmacophore

The molecular features that are necessary for interactions between a molecule or protein and its ligand.

Phenome-wide association studies

PheWASs. Analysis of the association between disease manifestations, or phenotypes, and a genetic variant.

Genome-wide association studies

GWASs. Analysis of the association between a disease and genetic variants.

Perturbagens

Small molecules, peptides, or genetic modifications that can induce changes in cell types, including cellular phenotypes, protein make-up and gene expression patterns.

Autoencoder

A type of artificial neural network that is used to learn to efficiently classify data in an unsupervised manner.

Perturbational studies

Studies designed to examine the response of cells to various interventions, including drugs and genetic alterations, for the purpose of understanding mechanism of action, changes in phenotype, gene expression or toxicity.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kingsmore, K.M., Grammer, A.C. & Lipsky, P.E. Drug repurposing to improve treatment of rheumatic autoimmune inflammatory diseases. Nat Rev Rheumatol 16, 32–52 (2020). https://doi.org/10.1038/s41584-019-0337-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41584-019-0337-0

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research