J Rheum Dis.  2020 Jul;27(3):128-135. 10.4078/jrd.2020.27.3.128.

Mechanism-based Drug Therapy of Inflammatory Bowel Disease With Special Reference to Rheumatic Disease

• Park JJ

• KMID: 2504028
• DOI: http://doi.org/10.4078/jrd.2020.27.3.128

Abstract

Inflammatory bowel disease (IBD), comprised of Crohn’s disease and ulcerative colitis, is a chronic, relapsing, and remitting disease of the gastrointestinal tract whose incidence is rising worldwide, especially in East Asian countries. The etiopathogenesis of IBD remains poorly understood. It is currently considered that a combination of genetic and environmental factors triggers an aberrant immune response against the commensal intestinal flora in IBD patients. Over the past decades, advances in the knowledge of the inflammatory cascade involved in IBD pathogenesis have expanded the pharmacological armamentarium in IBD. Actually, the introduction of specific biological therapies, including anti- tumor necrosis factor, anti-interleukin- 12/23, and anti-integrin, has revolutionized the treatment of IBD. Moreover, small molecule agents such as Janus kinase inhibitors also now under clinical use. In IBD, a substantial number of patient accompanies various articular manifestations and, rheumatic involvement is one of the most common extra-intestinal symptoms. Many of the mechanisms based drugs described above have already been used in rheumatic diseases. In addition, some of those drugs can be used to treat both IBD itself and accompanied rheumatic involvement, however there are differences in drug usage between these two indications. This review aims to briefly review the mechanism-based drug therapies of IBD with particular reference to rheumatic disease.

Keyword

Inflammatory bowel disease; Crohn’s disease; Ulcerative colitis; Pathogenesis; Biologics; Small molecule

Reference

1. Ng SC, Shi HY, Hamidi N, Underwood FE, Tang W, Benchimol EI, et al. 2018; Worldwide incidence and prevalence of inflammatory bowel disease in the 21st century: a systematic review of population-based studies. Lancet. 390:2769–78. DOI: 10.1016/S0140-6736(17)32448-0.

2. Xavier RJ, Podolsky DK. 2007; Unravelling the pathogenesis of inflammatory bowel disease. Nature. 448:427–34. DOI: 10.1038/nature06005. PMID: 17653185.

3. Torres J, Mehandru S, Colombel JF, Peyrin-Biroulet L. 2017; Crohn's disease. Lancet. 389:1741–55. DOI: 10.1016/S0140-6736(16)31711-1. PMID: 27914655.

4. Ungaro R, Mehandru S, Allen PB, Peyrin-Biroulet L, Colombel JF. 2017; Ulcerative colitis. Lancet. 389:1756–70. DOI: 10.1016/S0140-6736(16)32126-2. PMID: 27914657. PMCID: PMC6487890.

5. Ott C, Schölmerich J. 2013; Extraintestinal manifestations and complications in IBD. Nat Rev Gastroenterol Hepatol. 10:585–95. DOI: 10.1038/nrgastro.2013.117. PMID: 23835489.

6. Atzeni F, Defendenti C, Ditto MC, Batticciotto A, Ventura D, Antivalle M, et al. 2014; Rheumatic manifestations in inflammatory bowel disease. Autoimmun Rev. 13:20–3. DOI: 10.1016/j.autrev.2013.06.006. PMID: 23774109.

7. Karreman MC, Luime JJ, Hazes JMW, Weel AEAM. 2017; The prevalence and incidence of axial and peripheral spondyloarthritis in inflammatory bowel disease: a systematic review and meta-analysis. J Crohns Colitis. 11:631–42. DOI: 10.1093/ecco-jcc/jjw199. PMID: 28453761.

8. Salvarani C, Fries W. 2009; Clinical features and epidemiology of spondyloarthritides associated with inflammatory bowel disease. World J Gastroenterol. 15:2449–55. DOI: 10.3748/wjg.15.2449. PMID: 19468993. PMCID: PMC2686901.

9. Palm O, Moum B, Ongre A, Gran JT. 2002; Prevalence of ankylosing spondylitis and other spondyloarthropathies among patients with inflammatory bowel disease: a population study (the IBSEN study). J Rheumatol. 29:511–5. PMID: 11908564.

10. Scarpa R, del Puente A, D'Arienzo A, di Girolamo C, della Valle G, Panarese A, et al. 1992; The arthritis of ulcerative colitis: clinical and genetic aspects. J Rheumatol. 19:373–7.

11. Dekker-Saeys BJ, Meuwissen SG, Van Den Berg-Loonen EM, De Haas WH, Meijers KA, Tytgat GN. 1978; Ankylosing spondylitis and inflammatory bowel disease. III. Clinical characteristics and results of histocompatibility typing (HLA B27) in 50 patients with both ankylosing spondylitis and inflammatory bowel disease. Ann Rheum Dis. 37:36–41. DOI: 10.1136/ard.37.1.36. PMID: 629602. PMCID: PMC1000186.

12. Orchard TR, Wordsworth BP, Jewell DP. 1998; Peripheral arthropathies in inflammatory bowel disease: their articular distribution and natural history. Gut. 42:387–91. DOI: 10.1136/gut.42.3.387. PMID: 9577346. PMCID: PMC1727027.

13. Orchard TR, Jewell DP. Targan SR, Shanahan F, Karp LC, editors. 2010. Conditions of the eyes and joints associated with inflammatory bowel disease. Inflammatory bowel disease: translating basic science into clinical practice. Blackwell;Chichester: p. 553–61.

14. Podolsky DK, Isselbacher KJ. 1983; Composition of human colonic mucin. Selective alteration in inflammatory bowel disease. J Clin Invest. 72:142–53. DOI: 10.1172/JCI110952. PMID: 6192143. PMCID: PMC1129169.

15. Schultsz C, Van Den Berg FM, Ten Kate FW, Tytgat GN, Dankert J. 1999; The intestinal mucus layer from patients with inflammatory bowel disease harbors high numbers of bacteria compared with controls. Gastroenterology. 117:1089–97. DOI: 10.1016/S0016-5085(99)70393-8. PMID: 10535871.

16. Wyatt J, Vogelsang H, Hübl W, Waldhöer T, Lochs H. 1993; Intestinal permeability and the prediction of relapse in Crohn's disease. Lancet. 341:1437–9. DOI: 10.1016/0140-6736(93)90882-H.

17. Brazil JC, Louis NA, Parkos CA. 2013; The role of polymorphonuclear leukocyte trafficking in the perpetuation of inflammation during inflammatory bowel disease. Inflamm Bowel Dis. 19:1556–65. DOI: 10.1097/MIB.0b013e318281f54e. PMID: 23598816. PMCID: PMC4110963.

18. Park JJ, Yang SK, Ye BD, Kim JW, Park DI, Yoon H, et al. IBD Study Group of the Korean Association for the Study of Intestinal Diseases. 2017; Second Korean guidelines for the management of Crohn's disease. Intest Res. 15:38–67. DOI: 10.5217/ir.2017.15.1.38. PMID: 28239314. PMCID: PMC5323307.

19. Choi CH, Moon W, Kim YS, Kim ES, Lee BI, Jung Y, et al. IBD Study Group of the Korean Association for the Study of Intestinal Diseases. 2017; Second Korean guidelines for the management of ulcerative colitis. Intest Res. 15:7–37. DOI: 10.5217/ir.2017.15.1.7. PMID: 28239313. PMCID: PMC5323310.

20. Bradley JR. 2008; TNF-mediated inflammatory disease. J Pathol. 214:149–60. DOI: 10.1002/path.2287. PMID: 18161752.

21. Slevin SM, Egan LJ. 2015; New insights into the mechanisms of action of anti-tumor necrosis factor-α monoclonal antibodies in inflammatory bowel disease. Inflamm Bowel Dis. 21:2909–20. DOI: 10.1097/MIB.0000000000000533. PMID: 26348448.

22. Grell M, Wajant H, Zimmermann G, Scheurich P. 1998; The type 1 receptor (CD120a) is the high-affinity receptor for soluble tumor necrosis factor. Proc Natl Acad Sci U S A. 95:570–5. DOI: 10.1073/pnas.95.2.570. PMID: 9435233. PMCID: PMC18461.

23. Billmeier U, Dieterich W, Neurath MF, Atreya R. 2016; Molecular mechanism of action of anti-tumor necrosis factor antibodies in inflammatory bowel diseases. World J Gastroenterol. 22:9300–13. DOI: 10.3748/wjg.v22.i42.9300. PMID: 27895418. PMCID: PMC5107694.

24. Targan SR, Hanauer SB, van Deventer SJ, Mayer L, Present DH, Braakman T, et al. 1997; A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn's disease. Crohn's Disease cA2 Study Group. N Engl J Med. 337:1029–35. DOI: 10.1056/NEJM199710093371502. PMID: 9321530.

25. Hanauer SB, Feagan BG, Lichtenstein GR, Mayer LF, Schreiber S, Colombel JF, et al. ACCENT I Study Group. 2002; Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet. 359:1541–9. DOI: 10.1016/S0140-6736(02)08512-4.

26. Sands BE, Anderson FH, Bernstein CN, Chey WY, Feagan BG, Fedorak RN, et al. 2004; Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med. 350:876–85. DOI: 10.1056/NEJMoa030815. PMID: 14985485.

27. Rutgeerts P, Sandborn WJ, Feagan BG, Reinisch W, Olson A, Johanns J, et al. 2005; Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med. 353:2462–76. DOI: 10.1056/NEJMoa050516. PMID: 16339095.

28. Hanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. 2006; Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 130:323–33. quiz 591DOI: 10.1053/j.gastro.2005.11.030. PMID: 16472588.

29. Colombel JF, Sandborn WJ, Rutgeerts P, Enns R, Hanauer SB, Panaccione R, et al. 2007; Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 132:52–65. DOI: 10.1053/j.gastro.2006.11.041. PMID: 17241859.

30. Sandborn WJ, van Assche G, Reinisch W, Colombel JF, D'Haens G, Wolf DC, et al. 2012; Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 142:257–65.e1-3. DOI: 10.1053/j.gastro.2011.10.032. PMID: 22062358.

31. Reinisch W, Sandborn WJ, Hommes DW, D'Haens G, Hanauer S, Schreiber S, et al. 2011; Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 60:780–7. DOI: 10.1136/gut.2010.221127. PMID: 21209123.

32. Sandborn WJ, Feagan BG, Marano C, Zhang H, Strauss R, Johanns J, et al. PURSUIT-SC Study Group. 2014; Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 146:85–95. quiz e14–5. DOI: 10.1053/j.gastro.2013.05.048. PMID: 23735746.

33. Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DG, Baerg RD, et al. 2001; Etanercept for active Crohn's disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology. 121:1088–94. DOI: 10.1053/gast.2001.28674. PMID: 11677200.

34. Van den Brande JM, Koehler TC, Zelinkova Z, Bennink RJ, te Velde AA, ten Cate FJ, et al. 2007; Prediction of antitumour necrosis factor clinical efficacy by real-time visualisation of apoptosis in patients with Crohn's disease. Gut. 56:509–17. DOI: 10.1136/gut.2006.105379. PMID: 17082252. PMCID: PMC1856870.

35. Monteleone G, Biancone L, Marasco R, Morrone G, Marasco O, Luzza F, et al. 1997; Interleukin 12 is expressed and actively released by Crohn's disease intestinal lamina propria mononuclear cells. Gastroenterology. 112:1169–78. DOI: 10.1016/S0016-5085(97)70128-8. PMID: 9098000.

36. Trinchieri G. 1994; Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood. 84:4008–27. DOI: 10.1182/blood.V84.12.4008.bloodjournal84124008. PMID: 7994020.

37. Neurath MF. 2014; Cytokines in inflammatory bowel disease. Nat Rev Immunol. 14:329–42. DOI: 10.1038/nri3661. PMID: 24751956.

38. Feagan BG, Sandborn WJ, Gasink C, Jacobstein D, Lang Y, Friedman JR, et al. UNITI-IM-UNITI Study Group. 2016; Ustekinumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 375:1946–60. DOI: 10.1056/NEJMoa1602773. PMID: 27959607.

39. Sands BE, Sandborn WJ, Panaccione R, O'Brien CD, Zhang H, Johanns J, et al. UNIFI Study Group. 2019; Ustekinumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 381:1201–14. DOI: 10.1056/NEJMoa1900750. PMID: 31553833.

40. Feagan BG, Panés J, Ferrante M, Kaser A, D'Haens GR, Sandborn WJ, et al. 2018; Risankizumab in patients with moderate to severe Crohn's disease: an open-label extension study. Lancet Gastroenterol Hepatol. 3:671–80. DOI: 10.1016/S2468-1253(18)30233-4. PMID: 30056030.

41. Sands BE, Chen J, Feagan BG, Penney M, Rees WA, Danese S, et al. 2017; Efficacy and safety of MEDI2070, an antibody against interleukin 23, in patients with moderate to severe Crohn's disease: a phase 2a study. Gastroenterology. 153:77–86.e6. DOI: 10.1053/j.gastro.2017.03.049. PMID: 28390867.

42. Sandborn WJ, Ferrante M, Bhandari BR, Berliba E, Feagan BG, Hibi T, et al. 2020; Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis. Gastroenterology. 158:537–49.e10. DOI: 10.1053/j.gastro.2019.08.043. PMID: 31493397.

43. Janssen Research & Development, LLC. 2019. Aug. 28. A study to evaluate the efficacy and safety of ustekinumab in the treatment of anti-TNF(alpha) refractory participants with active radiographic axial spondyloarthritis [Internet]. U.S. National Library of Medicine;Bethesda: Available from: https://clinicaltrials.gov/ct2/show/NCT02438787. cited 2020 Mar.

44. Janssen Research & Development, LLC. 2019. Mar. 13. An efficacy and safety study of ustekinumab in participants with active nonradiographic axial spondyloarthritis [Internet]. U.S. National Library of Medicine;Bethesda: Available from: https://clinicaltrials.gov/ct2/show/NCT02407223. cited 2020 Mar.

45. Witowski J, Książek K, Jörres A. 2004; Interleukin-17: a mediator of inflammatory responses. Cell Mol Life Sci. 61:567–79. DOI: 10.1007/s00018-003-3228-z. PMID: 15004696.

46. Hölttä V, Klemetti P, Sipponen T, Westerholm-Ormio M, Kociubinski G, Salo H, et al. 2008; IL-23/IL-17 immunity as a hallmark of Crohn's disease. Inflamm Bowel Dis. 14:1175–84. DOI: 10.1002/ibd.20475. PMID: 18512248.

47. Hueber W, Sands BE, Lewitzky S, Vandemeulebroecke M, Reinisch W, Higgins PD, et al. Secukinumab in Crohn's Disease Study Group. 2012; Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 61:1693–700. DOI: 10.1136/gutjnl-2011-301668. PMID: 22595313. PMCID: PMC4902107.

48. Lee JS, Tato CM, Joyce-Shaikh B, Gulen MF, Cayatte C, Chen Y, et al. 2015; Interleukin-23-independent IL-17 production regulates intestinal epithelial permeability. Immunity. 43:727–38. DOI: 10.1016/j.immuni.2015.09.003. PMID: 26431948. PMCID: PMC6044435.

49. Ito H, Takazoe M, Fukuda Y, Hibi T, Kusugami K, Andoh A, et al. 2004; A pilot randomized trial of a human anti-interleukin-6 receptor monoclonal antibody in active Crohn's disease. Gastroenterology. 126:989–96. discussion 947DOI: 10.1053/j.gastro.2004.01.012. PMID: 15057738.

50. Danese S, Vermeire S, Hellstern P, Panaccione R, Rogler G, Fraser G, et al. 2019; Randomised trial and open-label extension study of an anti-interleukin-6 antibody in Crohn's disease (ANDANTE I and II). Gut. 68:40–8. DOI: 10.1136/gutjnl-2017-314562. PMID: 29247068. PMCID: PMC6839832.

51. Zundler S, Neurath MF. 2017; Novel insights into the mechanisms of gut homing and antiadhesion therapies in inflammatory bowel diseases. Inflamm Bowel Dis. 23:617–27. DOI: 10.1097/MIB.0000000000001067. PMID: 28296823.

52. Feagan BG, Rutgeerts P, Sands BE, Hanauer S, Colombel JF, Sandborn WJ, et al. GEMINI 1 Study Group. 2013; Vedolizumab as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 369:699–710. DOI: 10.1056/NEJMoa1215734. PMID: 23964932.

53. Sandborn WJ, Feagan BG, Rutgeerts P, Hanauer S, Colombel JF, Sands BE, et al. GEMINI 2 Study Group. 2013; Vedolizumab as induction and maintenance therapy for Crohn's disease. N Engl J Med. 369:711–21. DOI: 10.1056/NEJMoa1215739. PMID: 23964933.

54. Lichtenstein GR, Hanauer SB, Sandborn WJ. 2012; Risk of biologic therapy-associated progressive multifocal leukoencephalopathy: use of the JC virus antibody assay in the treatment of moderate-to-severe Crohn's disease. Gastroenterol Hepatol (N Y). 8(11 Suppl 8):1–20.

55. Sandborn WJ, Yednock TA. 2003; Novel approaches to treating inflammatory bowel disease: targeting alpha-4 integrin. Am J Gastroenterol. 98:2372–82. DOI: 10.1111/j.1572-0241.2003.08703.x. PMID: 14638336.

56. Tadbiri S, Peyrin-Biroulet L, Serrero M, Filippi J, Pariente B, Roblin X, et al. GETAID OBSERV-IBD study group. 2018; Impact of vedolizumab therapy on extra-intestinal manifestations in patients with inflammatory bowel disease: a multicentre cohort study nested in the OBSERV-IBD cohort. Aliment Pharmacol Ther. 47:485–93. DOI: 10.1111/apt.14419. PMID: 29250803.

57. Orlando A, Orlando R, Ciccia F, Renna S, Rizzo A, Cottone M, et al. 2017; Clinical benefit of vedolizumab on articular manifestations in patients with active spondyloarthritis associated with inflammatory bowel disease. Ann Rheum Dis. 76:e31. DOI: 10.1136/annrheumdis-2016-211011. PMID: 28096071.

58. Feagan BG, Sandborn WJ, Colombel JF, Byrne SO, Khalid JM, Kempf C, et al. 2019; Incidence of arthritis/arthralgia in inflammatory bowel disease with long-term vedolizumab treatment: post hoc analyses of the GEMINI trials. J Crohns Colitis. 13:50–7. DOI: 10.1093/ecco-jcc/jjy125. PMID: 30203005. PMCID: PMC6302953.

59. Varkas G, Thevissen K, De Brabanter G, Van Praet L, Czul-Gurdian F, Cypers H, et al. 2017; An induction or flare of arthritis and/or sacroiliitis by vedolizumab in inflammatory bowel disease: a case series. Ann Rheum Dis. 76:878–81. DOI: 10.1136/annrheumdis-2016-210233. PMID: 27899374.

60. Wendling D, Sondag M, Verhoeven F, Vuitton L, Koch S, Prati C. 2018; Arthritis occurrence or reactivation under Vedolizumab treatment for inflammatory bowel disease. A four cases report. Joint Bone Spine. 85:255–6. DOI: 10.1016/j.jbspin.2017.01.012. PMID: 28238881.

61. Dubash S, Marianayagam T, Tinazzi I, Al-Araimi T, Pagnoux C, Weizman AV, et al. 2019; Emergence of severe spondyloarthropathy-related entheseal pathology following successful vedolizumab therapy for inflammatory bowel disease. Rheumatology (Oxford). 58:963–8. DOI: 10.1093/rheumatology/key267. PMID: 30204909.

62. Tamanini S, Fredi M, Crisafulli F, Lazzaroni MG, Tincani A, Franceschini F. 2019; Letter to editor: new onset/recurrence of inflammatory arthralgia/spondyloarthritis in patients treated with vedolizumab for intestinal bowel disease. Clin Rheumatol. 38:609–10. DOI: 10.1007/s10067-018-4357-y. PMID: 30397839.

63. Paccou J, Nachury M, Duchemin C, Desreumaux P, Flipo RM, Pariente B. 2019; Vedolizumab has no efficacy on articular manifestations in patients with spondyloarthritis associated with inflammatory bowel disease. Joint Bone Spine. 86:654–6. DOI: 10.1016/j.jbspin.2019.01.008. PMID: 30711690.

64. Peyrin-Biroulet L, Christopher R, Behan D, Lassen C. 2017; Modulation of sphingosine-1-phosphate in inflammatory bowel disease. Autoimmun Rev. 16:495–503. DOI: 10.1016/j.autrev.2017.03.007. PMID: 28279838.

65. Baker SJ, Rane SG, Reddy EP. 2007; Hematopoietic cytokine receptor signaling. Oncogene. 26:6724–37. DOI: 10.1038/sj.onc.1210757. PMID: 17934481.

66. Sandborn WJ, Su C, Panes J. 2017; Tofacitinib as induction and maintenance therapy for ulcerative colitis. N Engl J Med. 377:496–7. DOI: 10.1056/NEJMc1707500. PMID: 28770978.

67. Currie KS, Patel L, Sedillo KF. 2019; Small-molecule agents for the treatment of inflammatory bowel disease. Bioorg Med Chem Lett. 29:2034–41. DOI: 10.1016/j.bmcl.2019.06.042. PMID: 31266686.

68. Panés J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D'Haens G, et al. 2017; Tofacitinib for induction and maintenance therapy of Crohn's disease: results of two phase IIb randomised placebo-controlled trials. Gut. 66:1049–59. DOI: 10.1136/gutjnl-2016-312735. PMID: 28209624. PMCID: PMC5532457.

69. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al. 2017; Clinical remission in patients with moderate-to-severe Crohn's disease treated with filgotinib (the FITZROY study): results from a phase 2, double-blind, randomised, placebo-controlled trial. Lancet. 389:266–75. DOI: 10.1016/S0140-6736(16)32537-5. PMID: 27988142.

70. Sandborn WJ, Feagan BG, Panes J, D'Haens GR, Colombel JF, Zhou Q, et al. 2017; Safety and efficacy of ABT-494 (upadacitinib), an oral Jak1 inhibitor, as induction therapy in patients with Crohn's disease: results from celest. Gastroenterology. 152(Suppl 1):S1308–9. DOI: 10.1016/S0016-5085(17)34357-3.

71. Sands BE, Sandborn WJ, Feagan BG, Lichtenstein GR, Zhang H, Strauss R, et al. Peficitinib-UC Study Group. 2018; Peficitinib, an oral janus kinase inhibitor, in moderate-to-severe ulcerative colitis: results from a randomised, phase 2 study. J Crohns Colitis. 12:1158–69. DOI: 10.1093/ecco-jcc/jjy085. PMID: 29917064.

72. Boland BS, Vermeire S. 2017; Janus kinase antagonists and other novel small molecules for the treatment of Crohn's disease. Gastroenterol Clin North Am. 46:627–44. DOI: 10.1016/j.gtc.2017.05.015. PMID: 28838419. PMCID: PMC5643010.

73. Miao XP, Li JS, Ouyang Q, Hu RW, Zhang Y, Li HY. 2014; Tolerability of selective cyclooxygenase 2 inhibitors used for the treatment of rheumatological manifestations of inflammatory bowel disease. Cochrane Database Syst Rev. (10):CD007744. DOI: 10.1002/14651858.CD007744.pub2. PMID: 25340915.