Abstract
Gastrointestinal (GI) perforations are rare events in rheumatoid arthritis (RA) patients, but cause significant morbidity and mortality. Several studies indicate that RA patients may be at higher risk of GI perforation. Traditional RA treatments such as glucocorticoids and non-steroidal anti-inflammatory drugs increase the risk of perforation. In the past two decades, a new class of therapeutic agents called biologics has been added to the RA treatment armamentarium. Biologics are effective in controlling disease activity and are generally well tolerated; however, reports of GI perforations in association with biologics have arisen. In particular, drugs that inhibit the interleukin (IL)-6 cytokine receptor have demonstrated a higher risk of perforation compared with other therapies. Recent reports also suggest that janus kinase inhibitors may increase the risk of perforation, perhaps via downstream effects on IL-6 signaling. In this review, we discuss current data on the risk of GI perforations among RA patients receiving targeted therapies and its clinical relevance.
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References
Young A, Koduri G. Extra-articular manifestations and complications of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2007;21(5):907–27.
Wallis D. Infection risk and biologics: current update. Curr Opin Rheumatol. 2014;26(4):404–9.
Jacobs DO. Clinical practice. Diverticulitis. N Engl J Med. 2007;357(20):2057–66.
Vermeulen J, van der Harst E, Lange JF. Pathophysiology and prevention of diverticulitis and perforation. Neth J Med. 2010;68(10):303–9.
Tridente A, Clarke GM, Walden A, McKechnie S, Hutton P, Mills GH, et al. Patients with faecal peritonitis admitted to European intensive care units: an epidemiological survey of the GenOSept cohort. Intensive Care Med. 2014;40(2):202–10.
Morris AM, Regenbogen SE, Hardiman KM, Hendren S. Sigmoid diverticulitis: a systematic review. JAMA. 2014;311(3):287–97.
Horton KM, Corl FM, Fishman EK. CT evaluation of the colon: inflammatory disease. Radiographics. 2000;20(2):399–418.
Biondo S, Trenti L, Elvira J, Golda T, Kreisler E. Outcomes of colonic diverticulitis according to the reason of immunosuppression. Am J Surg. 2016;212(3):384–90.
Pessaux P, Muscari F, Ouellet JF, Msika S, Hay JM, Millat B, et al. Risk factors for mortality and morbidity after elective sigmoid resection for diverticulitis: prospective multicenter multivariate analysis of 582 patients. World J Surg. 2004;28(1):92–6.
Curtis JR, Lanas A, John A, Johnson DA, Schulman KL. Factors associated with gastrointestinal perforation in a cohort of patients with rheumatoid arthritis. Arthritis Care Res. 2012;64(12):1819–28.
Hernández-Díaz S, Rodríguez LA. Association between nonsteroidal anti-inflammatory drugs and upper gastrointestinal tract bleeding/perforation: an overview of epidemiologic studies published in the 1990s. Arch Intern Med. 2000;160(14):2093–9.
Larkai EN, Smith JL, Lidsky MD, Graham DY. Gastroduodenal mucosa and dyspeptic symptoms in arthritic patients during chronic nonsteroidal anti-inflammatory drug use. Am J Gastroenterol. 1987;82(11):1153–8.
Bardou M, Barkun AN. Preventing the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs: from risk factor identification to risk factor intervention. Jt Bone Spine. 2010;77(1):6–12.
Goldstein JL, Eisen GM, Lewis B, Gralnek IM, Zlotnick S, Fort JG, et al. Video capsule endoscopy to prospectively assess small bowel injury with celecoxib, naproxen plus omeprazole, and placebo. Clin Gastroenterol Hepatol. 2005;3(2):133–41.
Humes DJ, Fleming KM, Spiller RC, West J. Concurrent drug use and the risk of perforated colonic diverticular disease: a population-based case-control study. Gut. 2011;60(2):219–24.
Lanas A, Perez-Aisa MA, Feu F, Ponce J, Saperas E, Santolaria S, et al. A nationwide study of mortality associated with hospital admission due to severe gastrointestinal events and those associated with nonsteroidal antiinflammatory drug use. Am J Gastroenterol. 2005;100(8):1685–93.
Wallace JL. Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn’t the stomach digest itself? Physiol Rev. 2008;88(4):1547–65.
Rostom A, Muir K, Dubé C, Jolicoeur E, Boucher M, Joyce J, et al. Gastrointestinal safety of cyclooxygenase-2 inhibitors: a Cochrane Collaboration systematic review. Clin Gastroenterol Hepatol. 2007;5(7):818–28, 28.e1–5 (quiz 768).
Wallace JL, McKnight W, Reuter BK, Vergnolle N. NSAID-induced gastric damage in rats: requirement for inhibition of both cyclooxygenase 1 and 2. Gastroenterology. 2000;119(3):706–14.
Matsui H, Shimokawa O, Kaneko T, Nagano Y, Rai K, Hyodo I. The pathophysiology of non-steroidal anti-inflammatory drug (NSAID)-induced mucosal injuries in stomach and small intestine. J Clin Biochem Nutr. 2011;48(2):107–11.
Kefalakes H, Stylianides TJ, Amanakis G, Kolios G. Exacerbation of inflammatory bowel diseases associated with the use of nonsteroidal anti-inflammatory drugs: myth or reality? Eur J Clin Pharmacol. 2009;65(10):963–70.
Curtis JR, Xie F, Chen L, Spettell C, McMahan RM, Fernandes J, et al. The incidence of gastrointestinal perforations among rheumatoid arthritis patients. Arthritis Rheum. 2011;63(2):346–51.
Saag KG, Koehnke R, Caldwell JR, Brasington R, Burmeister LF, Zimmerman B, et al. Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events. Am J Med. 1994;96(2):115–23.
Mpofu S, Mpofu CM, Hutchinson D, Maier AE, Dodd SR, Moots RJ. Steroids, non-steroidal anti-inflammatory drugs, and sigmoid diverticular abscess perforation in rheumatic conditions. Ann Rheum Dis. 2004;63(5):588–90.
Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open. 2014;4(5):e004587.
Schäcke H, Döcke WD, Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther. 2002;96(1):23–43.
Genta MS, Genta RM, Gabay C. Systemic rheumatoid vasculitis: a review. Semin Arthritis Rheum. 2006;36(2):88–98.
Babian M, Nasef S, Soloway G. Gastrointestinal infarction as a manifestation of rheumatoid vasculitis. Am J Gastroenterol. 1998;93(1):119–20.
Bienenstock H, Minick CR, Rogoff B. Mesenteric arteritis and intestinal infarction in rheumatoid disease. Arch Intern Med. 1967;119(4):359–64.
Corsi F, Previde P, Colombo F, Cellerino P, Donati M, Trabucchi E. Two cases of intestinal perforation in patients on anti-rheumatic treatment with etanercept. Clin Exp Rheumatol. 2006;24(1):113.
Curtis JR, Chen SY, Werther W, John A, Johnson DA. Validation of ICD-9-CM codes to identify gastrointestinal perforation events in administrative claims data among hospitalized rheumatoid arthritis patients. Pharmacoepidemiol Drug Saf. 2011;20(11):1150–8.
Monemi S, Berber E, Sarsour K, Wang J, Lampl K, Bharucha K, et al. Incidence of gastrointestinal perforations in patients with rheumatoid arthritis treated with tocilizumab from clinical trial, postmarketing, and real-world data sources. Rheumatol Ther. 2016;3(2):337–52.
Xie F, Yun H, Bernatsky S, Curtis JR. Brief report: risk of gastrointestinal perforation among rheumatoid arthritis patients receiving tofacitinib, tocilizumab, or other biologic treatments. Arthritis Rheumatol. 2016;68(11):2612–7.
Curtis JR, Perez-Gutthann S, Suissa S, Napalkov P, Singh N, Thompson L, et al. Tocilizumab in rheumatoid arthritis: a case study of safety evaluations of a large postmarketing data set from multiple data sources. Semin Arthritis Rheum. 2015;44(4):381–8.
Závada J, Lunt M, Davies R, Low AS, Mercer LK, Galloway JB, et al. The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the BSRBR-RA. Ann Rheum Dis. 2014;73(1):252–5.
Fleischmann R, Rubbert-Roth A, Combe B, et al. FRI0173 Gastrointestinal perforations with certolizumab PEGOL. Ann Rheum Dis. 2013;71:370.
Navarro-Millán I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther. 2012;34(4):788–802.e3.
Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, 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. 2008;371(9617):987–97.
Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23.
Jones G, Sebba A, Gu J, Lowenstein MB, Calvo A, Gomez-Reino JJ, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88–96.
Gout T, Ostor AJ, Nisar MK. Lower gastrointestinal perforation in rheumatoid arthritis patients treated with conventional DMARDs or tocilizumab: a systematic literature review. Clin Rheumatol. 2011;30(11):1471–4.
Genovese MC, Rubbert-Roth A, Smolen JS, Kremer J, Khraishi M, Gómez-Reino J, et al. Longterm safety and efficacy of tocilizumab in patients with rheumatoid arthritis: a cumulative analysis of up to 4.6 years of exposure. J Rheumatol. 2013;40(6):768–80.
Lazzerini PE, Capecchi PL, Guidelli GM, Selvi E, Acampa M, Laghi-Pasini F. Spotlight on sirukumab for the treatment of rheumatoid arthritis: the evidence to date. Drug Des Devel Ther. 2016;10:3083–98.
Aletaha D, Bingham CO, Tanaka Y, Agarwal P, Kurrasch R, Tak PP, et al. Efficacy and safety of sirukumab in patients with active rheumatoid arthritis refractory to anti-TNF therapy (SIRROUND-T): a randomised, double-blind, placebo-controlled, parallel-group, multinational, phase 3 study. Lancet. 2017;389(10075):1206–17.
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.
Verheul HM, Lolkema MP, Qian DZ, Hilkes YH, Liapi E, Akkerman JW, et al. Platelets take up the monoclonal antibody bevacizumab. Clin Cancer Res. 2007;13(18 Pt 1):5341–7.
Verheul HM, Pinedo HM. Possible molecular mechanisms involved in the toxicity of angiogenesis inhibition. Nat Rev Cancer. 2007;7(6):475–85.
Schmidinger M. Understanding and managing toxicities of vascular endothelial growth factor (VEGF) inhibitors. EJC Suppl. 2013;11(2):172–91.
Gyires K. Gastric mucosal protection: from prostaglandins to gene-therapy. Curr Med Chem. 2005;12(2):203–15.
Nakahara H, Song J, Sugimoto M, Hagihara K, Kishimoto T, Yoshizaki K, et al. Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum. 2003;48(6):1521–9.
Kuhn KA, Manieri NA, Liu TC, Stappenbeck TS. IL-6 stimulates intestinal epithelial proliferation and repair after injury. PLoS One. 2014;9(12):e114195.
Strangfeld A, Richter A, Siegmund B, Herzer P, Rockwitz K, Demary W, et al. Risk for lower intestinal perforations in patients with rheumatoid arthritis treated with tocilizumab in comparison to treatment with other biologic or conventional synthetic DMARDs. Ann Rheum Dis. 2017;76(3):504–10.
Migita K, Izumi Y, Jiuchi Y, Kozuru H, Kawahara C, Izumi M, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 during treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208–14.
Geirsson AJ, Sturfelt G, Truedsson L. Clinical and serological features of severe vasculitis in rheumatoid arthritis: prognostic implications. Ann Rheum Dis. 1987;46(10):727–33.
Hart AR, Kennedy HJ, Stebbings WS, Day NE. How frequently do large bowel diverticula perforate? An incidence and cross-sectional study. Eur J Gastroenterol Hepatol. 2000;12(6):661–5.
Chapman J, Davies M, Wolff B, Dozois E, Tessier D, Harrington J, et al. Complicated diverticulitis: is it time to rethink the rules? Ann Surg. 2005;242(4):576–81 (discussion 81–83).
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Aprajita Jagpal has no conflicts of interest to declare. Jeffrey Curtis has received research grants and consulting fees for unrelated work from Pfizer, Amgen, Abbvie, Corrona, Crescendo, BMS, Janssen, Sanofi-Regeneron, and Roche.
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Jagpal, A., Curtis, J.R. Gastrointestinal Perforations with Biologics in Patients with Rheumatoid Arthritis: Implications for Clinicians. Drug Saf 41, 545–553 (2018). https://doi.org/10.1007/s40264-018-0639-1
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DOI: https://doi.org/10.1007/s40264-018-0639-1