Advertisement

Safety of treatments for inflammatory bowel disease: Clinical practice guidelines of the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD)

Published:January 17, 2017DOI:https://doi.org/10.1016/j.dld.2017.01.141

      Abstract

      Inflammatory bowel diseases are chronic conditions of unknown etiology, showing a growing incidence and prevalence in several countries, including Italy. Although the etiology of Crohn’s disease and ulcerative colitis is unknown, due to the current knowledge regarding their pathogenesis, effective treatment strategies have been developed. Several guidelines are available regarding the efficacy and safety of available drug treatments for inflammatory bowel diseases. Nevertheless, national guidelines provide additional information adapted to local feasibility, costs and legal issues related to the use of the same drugs. These observations prompted the Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) to establish Italian guidelines on the safety of currently available treatments for Crohn’s disease and ulcerative colitis. These guidelines discuss the use of aminosalicylates, systemic and low bioavailability corticosteroids, antibiotics (metronidazole, ciprofloxacin, rifaximin), thiopurines, methotrexate, cyclosporine A, TNFα antagonists, vedolizumab, and combination therapies. These guidelines are based on current knowledge derived from evidence-based medicine coupled with clinical experience of a national working group.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Digestive and Liver Disease
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Summers R.W.
        • Switz D.M.
        • Sessions J.T.
        • et al.
        National Cooperative Crohn’s Disease Study: results of drug treatment.
        Gastroenterology. 1979; 77: 847-869
        • Malchow H.
        • Ewe K.
        • Brandes J.W.
        • et al.
        European Co-operative Crohn’s Disease Study (ECCDS): results of drug treatment.
        Gastroenterology. 1984; 86: 249-266
        • Truelove S.C.
        • Witts L.J.
        Cortisone in ulcerative colitis; final report on a therapeutic trial.
        British Medical Journal. 1955; 2: 1041-1048
        • Rosenberg W.
        • Ireland A.
        • Jewell D.P.
        High-dose methylprednisolone in the treatment of active ulcerative colitis.
        Journal of Clinical Gastroenterology. 1990; 12: 40-41
        • Bossa F.
        • Fiorella S.
        • Caruso N.
        • et al.
        Continuous infusion versus bolus administration of steroids in severe attacks of ulcerative colitis: a randomized, double-blind trial.
        American Journal of Gastroenterology. 2007; 102: 601-608
        • Dignass A.
        • Van Assche G.
        • Lindsay J.O.
        • et al.
        The second European evidence-based consensus on the diagnosis and management of Crohn’s disease: current management.
        Journal of Crohn’s and Colitis. 2010; 4: 28-62
        • Dignass A.
        • Lindsay J.O.
        • Sturm A.
        • et al.
        Second European evidence-based consensus on the diagnosis and management of ulcerative colitis part 2: current management.
        Journal of Crohn’s and Colitis. 2012; 6: 991-1030
        • Tremaine W.J.
        • Schroeder K.W.
        • Harrison J.M.
        • et al.
        A randomized, double-blind, placebo-controlled trial of the oral mesalamine (5-ASA) preparation, Asacol, in the treatment of symptomatic Crohn’s colitis and ileocolitis.
        Journal of Clinical Gastroenterology. 1994; 19: 278-282
        • Singleton J.W.
        • Hanauer S.B.
        • Gitnick G.L.
        • et al.
        Mesalamine capsules for the treatment of active Crohn’s disease: results of a 16-week trial.
        Gastroenterology. 1993; 104: 1293-1301
        • Cortot A.
        • Colombel J.F.
        • Rutgeerts P.
        Switch from systemic steroids to budesonide in steroid dependent patients with inactive Crohn’s disease.
        Gut. 2001; 48: 186-190
        • Sandborn W.J.
        • Löfberg R.
        • Feagan B.G.
        • et al.
        Budesonide for maintenance of remission in patients with Crohn’s disease in medically induced remission: a predetermined pooled analysis of four randomized, double-blind, placebo-controlled trials.
        American Journal of Gastroenterology. 2005; 100: 1780-1787
        • Campieri M.
        • Adamo S.
        • Valpiani D.
        • et al.
        Oral beclometasone dipropionate in the treatment of extensive and left-sided active ulcerative colitis: a multicentre randomised study.
        Alimentary Pharmacology & Therapeutics. 2003; 17: 1471-1480
        • Sutherland L.R.
        • Singleton J.
        • Sessions J.
        • et al.
        Double-blind, placebo-controlled trial of metronidazole in Crohn’s disease.
        Gut. 1991; 32: 1071-1075
        • Colombel J.F.
        • Lemann M.
        • Cassagnou M.
        • et al.
        A controlled trial comparing ciprofloxacin with mesalazine for the treatment of active Crohn’s disease.
        American Journal of Gastroenterology. 1999; 94: 674-678
        • Prantera C.
        • Zannoni F.
        • Scribano M.L.
        • et al.
        An antibiotic regimen for the treatment of active Crohn’s disease: a randomized, controlled clinical trial of metronidazole plus ciprofloxacin.
        American Journal of Gastroenterology. 1996; 91: 328-332
        • Candy S.
        • Wright J.
        • Gerber M.
        • et al.
        A controlled double blind study of azathioprine in the management of Crohn’s disease.
        Gut. 1995; 37: 674-678
        • Lémann M.
        • Mary J.Y.
        • Colombel J.-F.
        • et al.
        A randomized, double-blind, controlled withdrawal trial in Crohn’s disease patients in long-term remission on azathioprine.
        Gastroenterology. 2005; 128: 1812-1818
        • Willoughby J.M.
        • Beckett J.
        • Kumar P.J.
        • et al.
        Controlled trial of azathioprine in Crohn’s disease.
        Lancet. 1971; ii: 944-947
        • Rosenberg J.L.
        • Levin B.
        • Wall A.J.
        • et al.
        A controlled trial of azathioprine in Crohn’s disease.
        American Journal of Digestive Diseases. 1975; 20: 721-726
        • O’Donoghue D.P.
        • Dawson A.M.
        • Powell-Tuck J.
        • et al.
        Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease.
        Lancet. 1978; ii: 955-957
        • Feagan B.G.
        • Fedorak R.N.
        • Irvine E.J.
        • et al.
        A comparison of methotrexate with placebo for the maintenance of remission in Crohn’s disease. North American Crohn’s Study Group Investigators.
        New England Journal of Medicine. 2000; 342: 1627-1632
        • D’Haens G.
        • Lemmens L.
        • Geboes K.
        • et al.
        Intravenous cyclosporine versus intravenous corticosteroids as single therapy for severe attacks of ulcerative colitis.
        Gastroenterology. 2001; 120: 1323-1329
        • Van Assche G.
        • D’Haens G.
        • Noman M.
        • et al.
        Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis.
        Gastroenterology. 2003; 125: 1025-1031
        • van Dullemen H.M.
        • van Deventer S.J.
        • Hommes D.W.
        • et al.
        Treatment of Crohn’s disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2).
        Gastroenterology. 1995; 109: 129-135
        • Targan S.R.
        • Hanauer S.B.
        • van Deventer S.J.
        • et al.
        A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor alpha for Crohn’s disease. Crohn’s Disease cA2 Study Group.
        New England Journal of Medicine. 1997; 337: 1029-1035
        • Schnitzler F.
        • Fidder H.
        • Ferrante M.
        • et al.
        Long-term outcome of treatment with infliximab in 614 patients with Crohn’s disease: results from a single-centre cohort.
        Gut. 2009; 58: 492-500
        • Rutgeerts P.
        • Sandborn W.J.
        • Feagan B.G.
        • et al.
        Infliximab for induction and maintenance therapy for ulcerative colitis.
        New England Journal of Medicine. 2005; 353: 2462-2476
        • Hanauer S.B.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn’s disease: the CLASSIC-I trial.
        Gastroenterology. 2006; 130: 323-333
        • Sandborn W.J.
        • Rutgeerts P.
        • Enns R.
        • et al.
        Adalimumab induction therapy for Crohn disease previously treated with infliximab: a randomized trial.
        Annals of Internal Medicine. 2007; 146: 829-838
        • Sandborn W.J.
        • van Assche G.
        • Reinisch W.
        • et al.
        Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis.
        Gastroenterology. 2012; 142: 257-265
        • Sandborn W.J.
        • Feagan B.G.
        • Marano C.
        • et al.
        Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.
        Gastroenterology. 2014; 146: 85-95
        • Papamichael K.
        • Van Stappen T.
        • Jairath V.
        • et al.
        Review article: pharmacological aspects of anti-TNF infliximab biosimilars in inflammatory bowel diseases.
        Alimentary Pharmacology & Therapeutics. 2015; 42: 1158-1169
        • Fiorino G.
        • Girolomoni G.
        • Lapadula G.
        • et al.
        The use of biosimilars in immune-mediated disease: a joint Italian Society of Rheumatology (SIR), Italian Society of Dermatology (SIDeMaST), and Italian Group of Inflammatory Bowel Disease (IG-IBD) position paper.
        Autoimmunity Reviews. 2014; 13: 751-755
        • Feagan B.G.
        • Rutgeerts P.
        • Sands B.E.
        • et al.
        Vedolizumab as induction and maintenance therapy for ulcerative colitis.
        New England Journal of Medicine. 2013; 369: 699-710
        • Bernstein C.N.
        • Fried M.
        • Krabshuis J.H.
        • et al.
        World Gastroenterology Organization practice guidelines for the diagnosis and management of IBD in 2010.
        Inflammatory Bowel Diseases. 2010; 16: 112-124
        • Orlando A.
        • Armuzzi A.
        • Papi C.
        • et al.
        The Italian Society of Gastroenterology (SIGE) and the Italian Group for the study of Inflammatory Bowel Disease (IG-IBD) Clinical Practice Guidelines: the use of tumor necrosis factor-alpha antagonist therapy in inflammatory bowel disease.
        Digestive and Liver Disease. 2011; 43: 1-20
      1. OCEBM Levels of Evidence Working Group. The Oxford 2011 levels of evidence. Oxford Centre for Evidence-Based Medicine 2011; http://www.cebm.net /1433 index.aspx?o=5653.

        • Svartz N.
        Salazypyrin, a new sulfanilamide preparation. A. Therapeutic results in rheumatic polyarthritis. B. Therapeutic results in ulcerative colitis. C. Toxic manifestations in treatment with sulfanilamide preparation.
        Acta Medica Scandinavica. 1942; 110: 557-590
        • Azad Khan A.K.
        • Piris J.
        • Truelove S.C.
        An experiment to determine the active therapeutic moiety of sulphasalazine.
        Lancet. 1977; 2: 892-895
        • Loftus Jr., E.V.
        • Kane S.V.
        • Bjorkman D.
        Systematic review: short term adverse effects of 5-aminosalicylic acid agents in the treatment of ulcerative colitis.
        Alimentary Pharmacology & Therapeutics. 2004; 19: 179-189
        • Feagan B.G.
        • MacDonald J.K.
        Oral aminosalicylic acid for induction of remission 1444 in ulcerative colitis (Review).
        Cochrane Database of Systematic Review. 2012; 10 (CD000544)
        • Feagan B.G.
        • Chande N.
        • MacDonald J.K.
        Are there any differences in the efficacy and safety of different formulations of oral 5-ASA used for induction and maintenance of remission in ulcerative colitis? Evidence from Cochrane reviews.
        Inflammatory Bowel Diseases. 2013; 19: 2031-2040
        • Kamm M.A.
        • Sandborn W.J.
        • Gassull M.
        • et al.
        Once daily, high concentration MMX mesalamine in active ulcerative colitis.
        Gastroenterology. 2007; 132: 66-75
        • Netzer P.
        Diffuse alopecia as side effect of mesalazine therapy in Crohn’s disease.
        Schweizerische Medizinische Wochenschrift. 1995; 125: 2438-2442
        • Watkinson G.
        Sulphasalazine: a review of 40 years’ experience.
        Drugs. 1986; 32: 1-11
        • Poland G.A.
        • Love K.R.
        Marked atypical lymphocytosis, hepatitis, and skin rash in sulfasalazine drug allergy.
        American Journal of Medicine. 1986; 81: 707-708
        • Mihas A.A.
        • Goldenberg D.J.
        • Slaughter R.L.
        Sulfasalazine toxic reactions. Hepatitis, fever, and skin rash with hypocomplementemia and immune complexes.
        JAMA. 1978; 239: 2590-2591
        • Smith M.D.
        • Gibson G.E.
        • Rowland R.
        Combined hepatotoxicity and neurotoxicity following sulphasalazine administration.
        Australian and New Zealand Journal of Medicine. 1982; 12: 76-80
        • Han T.
        • Chawla P.L.
        • Sokal J.E.
        Sulfapyridine-induced serum sickness-like syndrome associated with plasmacytosis, lymphocytosis and multiclonal gamma-globulinopathy.
        New England Journal of Medicine. 1969; 280: 547-548
        • Tisdale W.A.
        Focal hepatitis, fever and skin rash following therapy with sulfamethoxypyridazine, a long-acting sulfonamide.
        New England Journal of Medicine. 1958; 258: 687-690
        • Faintuch J.
        • Mott C.B.
        • Machado M.C.
        Pancreatitis and pancreatic necrosis during sulfasalazine therapy.
        International Surgery. 1985; 70: 271-272
        • Rubin R.
        Sulfasalazine-induced fulminant hepatic failure and necrotizing pancreatitis.
        American Journal of Gastroenterology. 1994; 89: 789-791
        • Garau P.
        • Orenstein S.R.
        • Neigut D.A.
        • et al.
        Pancreatitis associated with olsalazine and sulfasalazine in children with ulcerative colitis.
        Journal of Pediatric Gastroenterology and Nutrition. 1994; 18: 481-485
        • Debongnie J.C.
        • Dekoninck X.
        Sulfasalazine, 5-ASA and acute pancreatitis in Crohn’s disease.
        Journal of Clinical Gastroenterology. 1994; 19: 348-349
        • Munk E.M.
        • Pedersen L.
        • Floyd A.
        • et al.
        Inflammatory bowel diseases, 5-aminosalicylic acid and sulfasalazine treatment and risk of acute pancreatitis: a population-based case-control study.
        American Journal of Gastroenterology. 2004; 99: 884-888
        • Lancashire R.J.
        • Cheng K.
        • Langman M.J.
        Discrepancies between population-based data and adverse reaction reports in assessing drugs as causes of acute pancreatitis.
        Alimentary Pharmacology & Therapeutics. 2003; 17: 887-893
        • Douros A.
        • Bronder E.
        • Andersohn F.
        • et al.
        Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases.
        Alimentary Pharmacology & Therapeutics. 2013; 38: 825-834
        • Mallory A.
        • Kern Jr., F.
        Drug-induced pancreatitis: a critical review.
        Gastroenterology. 1980; 78: 813-820
        • Block M.B.
        • Genant H.K.
        • Kirsner J.B.
        Pancreatitis as an adverse reaction to salicylazosulfapyridine.
        New England Journal of Medicine. 1970; 282: 380-382
        • Das K.M.
        • Eastwood M.A.
        • McManus J.P.
        • et al.
        Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype.
        New England Journal of Medicine. 1973; 289: 491-495
        • Daneshmend T.K.
        Mesalazine associated thrombocytopenia.
        Lancet. 1991; 337: 1297-1298
        • Casellas F.
        • Vallano A.
        • Malagelada J.R.
        Leukopenia and thrombocytopenia as adverse effects of treatment with 5-aminosalicyclic suppositories.
        Journal of Clinical Gastroenterology. 1996; 22: 160-161
        • Wyatt S.
        • Joyner M.V.
        • Daneshmend T.K.
        Filgastrim for mesalazine-associated neutropenia.
        Lancet. 1993; 341: 1476
        • Turunen U.
        • Elomaa I.
        • Anthla V.I.
        • et al.
        Mesalazine tolerance in patients with inflammatory bowel disease and previous intolerance or allergy to sulphasalazine or sulphonamides.
        Scandinavian Journal of Gastroenterology. 1987; 22: 798-802
        • Laidlaw S.T.
        • Reilly J.T.
        Antilymphocyte globulin for mesalazine-associated aplastic anemia.
        Lancet. 1994; 343: 981-982
        • Abboudi Z.H.
        • Marsh J.C.
        • Smith-Long G.
        • et al.
        Fatal aplastic anemia after mesalazine.
        Lancet. 1994; 343 ([letter]): 542
        • Bernstein C.N.
        • Wajda A.
        • Blanchard J.F.
        The clustering of other chronic inflammatory diseases in inflammatory bowel disease: a population-based study.
        Gastroenterology. 2005; 129: 827-836
        • Ishikawa N.
        • Imamura T.
        • Nakajima K.
        • et al.
        Acute pericarditis associated with 5-aminosalicylic acid (5-ASA) treatment for severe active ulcerative colitis.
        Internal Medicine. 2001; 40: 901-904
        • Sentongo T.A.
        • Piccoli D.A.
        Recurrent pericarditis due to mesalamine hypersensitivity: a pediatric case report and review of the literature.
        Journal of Pediatric Gastroenterology and Nutrition. 1998; 27: 344-347
        • Perrot S.
        • Aslangul E.
        • Szwebel T.
        • et al.
        Sulfasalazine-induced pericarditis in a patient with ulcerative colitis without recurrence when switching to mesalazine.
        International Journal of Colorectal Disease. 2007; 22: 1119-1121
        • Baker D.E.
        • Kane S.
        The short- and long-term safety of 5-aminosalicylate products in the treatment of ulcerative colitis.
        Reviews in Gastroenterological Disorders. 2004; 4: 86-91
        • Di Paolo M.C.
        • Paoluzi O.A.
        • Pica R.
        • et al.
        Sulphasalazine and 5-aminosalicylic acid in long-term treatment of ulcerative colitis: report on tolerance and side-effects.
        Digestive and Liver Disease. 2001; 33: 563-569
        • Heap G.A.
        • So K.
        • Weedon M.
        • et al.
        Clinical features and HLA association of 5-aminosalicylate (5-ASA)-induced nephrotoxicity in inflammatory bowel disease.
        Journal of Crohn’s and Colitis. 2016; 10: 149-158
        • Muller A.F.
        • Stevens P.E.
        • McIntyre A.S.
        • et al.
        Experience of 5-aminosalicylate nephrotoxicity in the United Kingdom.
        Alimentary Pharmacology & Therapeutics. 2005; 21: 1217-1224
        • Dehmer C.
        • Greinwald R.
        • Löffler J.
        No dose-dependent tubulotoxicity of 5-aminosalicylic acid: a prospective study in patients with inflammatory bowel diseases.
        International Journal of Colorectal Disease. 2003; 18: 406-412
        • Elseviers M.M.
        • D’Haens G.
        • Lerebours E.
        • et al.
        Renal impairment in patients with inflammatory bowel disease: association with aminosalicylate therapy?.
        Clinical Nephrology. 2004; 61: 83-89
        • Travis S.P.
        • Stange E.F.
        • Lemann M.
        • et al.
        European evidence-based consensus on the management of ulcerative colitis: current management.
        Journal of Crohn’s and Colitis. 2008; 2: 24-62
        • Kornbluth A.
        • Sachar D.B.
        Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee.
        American Journal of Gastroenterology. 2010; 105: 501-523
        • Van Staa T.P.
        • Travis S.
        • Leufkens H.G.
        • et al.
        5-Aminosalicylic acids and the risk of renal disease: a large British epidemiologic study.
        Gastroenterology. 2004; 126: 1733-1739
        • Corrigan G.
        • Stevens P.E.
        Review article: interstitial nephritis associated with the use of mesalazine in inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2000; 14: 1-6
        • World M.J.
        • Stevens P.E.
        • Ashton M.A.
        • et al.
        Mesalazine associated interstitial nephritis.
        Nephrology Dialysis Transplantation. 1996; 11: 614-621
        • Cunliffe R.N.
        • Scott B.B.
        Review article: monitoring for drug side-effects in inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2002; 16: 647-662
        • Gisbert J.P.
        • Gonzalez-Lama Y.
        • Mate J.
        5-Aminosalicylates and renal function in inflammatory bowel disease: a systematic review.
        Inflammatory Bowel Diseases. 2007; 13: 629-638
        • Sannerstedt R.
        • Lundborg P.
        • Danielsson B.R.
        • et al.
        Drugs during pregnancy: an issue of risk classification and information to prescribers.
        Drug Safety. 1996; 14: 69-77
        • Marteau P.
        • Tennenbaum R.
        • Elefant E.
        • et al.
        Foetal outcome in women with inflammatory bowel disease treated during pregnancy with oral mesalazine microgranules.
        Alimentary Pharmacology & Therapeutics. 1998; 12: 1101-1108
        • Diav-Citrin O.
        • Park Y.H.
        • Veerasuntharam G.
        • et al.
        The safety of mesalamine in human pregnancy: a prospective controlled cohort study.
        Gastroenterology. 1998; 114: 23-28
        • Marteau P.
        • Devaux C.B.
        Mesalazine during pregnancy.
        Lancet. 1994; 344: 1708-1709
        • Sachar D.
        Exposure to mesalamine during pregnancy increased preterm deliveries (but not birth defects) and decreased birth weight.
        Gut. 1998; 43: 316
        • Nørgård B.
        • Fonager K.
        • Pedersen L.
        • et al.
        Birth outcome in women exposed to 5-aminosalicylic acid during pregnancy: a Danish cohort study.
        Gut. 2003; 52: 243-247
        • Nørgård B.
        • Pedersen L.
        • Christensen L.A.
        • et al.
        Therapeutic drug use in women with Crohn’s disease and birth outcomes: a Danish nationwide cohort study.
        American Journal of Gastroenterology. 2007; 102: 1406-1413
        • Ban L.
        • Tata L.J.
        • Fiaschi L.
        • et al.
        Limited risks of major congenital anomalies in children of mothers with IBD and effects of medications.
        Gastroenterology. 2014; 146: 76-84
        • Marteau P.
        • Seksik P.
        • Couve S.
        • et al.
        Safety of high doses of mesalazine during pregnancy.
        American Journal of Gastroenterology. 2005; 100: 1897-1898
        • Rahimi R.
        • Nikfar S.
        • Rezaie A.
        • et al.
        Pregnancy outcome in women with inflammatory bowel disease following exposure to 5-aminosalicylic acid drugs: a meta-analysis.
        Reproductive Toxicology. 2008; 25: 271-275
        • Moffatt D.C.
        • Bernstein C.N.
        Drug therapy for inflammatory bowel disease in pregnancy and the puerperium.
        Best Practice & Research Clinical Gastroenterology. 2007; 21: 835-847
      2. Position paper Agenzia Italiana per il Farmaco (AIFA), 2013.

        • Peppa M.
        • Krania M.
        • Raptis S.A.
        Hypertension and other morbidities with Cushing’s syndrome associated with corticosteroids: a review.
        Integrated Blood Pressure Control. 2011; 4: 7-16
        • Whitworth J.A.
        • Williamson P.M.
        • Mangos G.
        • et al.
        Cardiovascular consequences of cortisol excess.
        Vascular Health and Risk Management. 2005; 1: 291-299
        • Da Silva J.A.
        • Jacobs J.W.
        • Kirwan J.R.
        • et al.
        Safety of low dose glucocorticoid treatment in rheumatoid arthritis: published evidence and prospective trial data.
        Annals of the Rheumatic Diseases. 2006; 65: 285-293
        • Sherlock M.E.
        • Seow C.H.
        • Steinhart A.H.
        • et al.
        Oral budesonide for induction of remission in ulcerative colitis.
        Cochrane Database of Systematic Reviews. 2010; : CD007698
        • Toruner M.
        • Loftus Jr., E.V.
        • Harmsen W.S.
        • et al.
        Risk factors for opportunistic infections in patients with inflammatory bowel disease.
        Gastroenterology. 2008; 134: 929-936
        • Rahier J.F.
        • Magrob F.
        • Abreue C.
        • et al.
        Second European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease.
        Journal of Crohn’s and Colitis. 2014; 8: 443-468
        • van Staa T.P.
        • Leufkens H.G.
        • Cooper C.
        The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis.
        Osteoporosis International. 2002; 13: 777-787
        • Ström O.
        • Borgström F.
        • Kanis J.A.
        • et al.
        Osteoporosis: burden, health care provision and opportunities in the EU: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA).
        Archives of Osteoporosis. 2011; 6: 59-155
        • Hauzeur J.
        • Malaise M.
        • Gangji V.
        Osteonecrosis in inflammatory bowel diseases: a review of the literature.
        Acta Gastro-Enterologica Belgica. 2009; 72: 327-334
        • Subramanian V.
        • Saxena S.
        • Kang J.Y.
        • et al.
        Preoperative steroid use and risk of postoperative complications in patients with inflammatory bowel disease undergoing abdominal surgery.
        American Journal of Gastroenterology. 2008; 103: 2373-2381
        • Aberra F.N.
        • Lewis J.D.
        • Hass D.
        • et al.
        Corticosteroids and immunomodulators: postoperative infectious complication risk in inflammatory bowel disease patients.
        Gastroenterology. 2003; 125: 320-327
        • Ferrante M.
        • D’Hoore A.
        • Vermeire S.
        • et al.
        Corticosteroids but not infliximab increase short-term postoperative infectious complications in patients with ulcerative colitis.
        Inflammatory Bowel Disease. 2009; 15: 1062-1070
        • van der Woude C.J.
        • Sanja Kolacek S.
        • Dotan I.
        • et al.
        European evidenced-based consensus on reproduction in inflammatory bowel disease.
        Journal of Crohn’s and Colitis. 2010; 4: 493-510
        • Bortoli A.
        • Pedersen N.
        • Duricova D.
        • et al.
        Pregnancy outcome in inflammatory bowel disease: prospective European case-control ECCO-EpiCom study, 2003–2006.
        Alimentary Pharmacology & Therapeutics. 2011; 34: 724-734
        • Day A.C.
        • Baio G.
        • Gazzard G.
        • et al.
        The prevalence of primary angle closure glaucoma in European derived populations: a systematic review.
        British Journal of Ophthalmology. 2012; 96: 1162-1167
        • Oray M.
        • Abu Samra K.
        • Ebrahimiadib N.
        • et al.
        Long-term side effects of glucocorticoids.
        Expert Opinion on Drug Safety. 2016; 15: 457-465
        • Lichtenstein G.R.
        • Feagan B.G.
        • Cohen R.D.
        • et al.
        Serious infections and mortality in association with therapies for Crohn’s disease: TREAT registry.
        Clinical Gastroenterology and Hepatology. 2006; 4: 621-630
        • Fascì Spurio F.
        • Aratari A.
        • Margagnoni G.
        • et al.
        Low bioavailability and traditional systemic steroids in IBD: can the former take over the latter?.
        Journal of Gastrointestinal and Liver Diseases. 2013; 22: 65-71
        • D’Haens G.R.
        • Kovács A.
        • Vergauwe P.
        • et al.
        Clinical trial: preliminary efficacy and safety study of a new Budesonide-MMX® 9 mg extended-release tablets in patients with active left-sided ulcerative colitis.
        Journal of Crohn’s and Colitis. 2010; 4: 153-160
        • Greenberg G.R.
        • Feagan B.G.
        • Martin F.
        • et al.
        Oral budesonide for active Crohn’s disease. Canadian Inflammatory Bowel Disease Study Group.
        New England Journal of Medicine. 1994; 331: 836-841
        • Tremaine W.J.
        • Hanauer S.B.
        • Katz S.
        • et al.
        Budesonide CIR capsules (once or twice daily divided-dose) in active Crohn’s disease: a randomized placebo-controlled study in the United States.
        American Journal of Gastroenterology. 2002; 97: 1748-1754
        • Tromm A.
        • Bunganič I.
        • Tomsová E.
        • et al.
        Budesonide 9 mg is at least as effective as mesalamine 4.5 g in patients with mildly to moderately active Crohn’s disease.
        Gastroenterology. 2011; 140 (e1): 425-434
        • Thomsen O.O.
        • Cortot A.
        • Jewell D.
        • et al.
        A comparison of budesonide and mesalamine for active Crohn’s disease. International Budesonide-Mesalamine Study Group.
        New England Journal of Medicine. 1998; 339 ([Erratum in: New England Journal of Medicine 2001;345:1652]): 370-374
        • Rutgeerts P.
        • Löfberg R.
        • Malchow H.
        • et al.
        A comparison of budesonide with prednisolone for active Crohn’s disease.
        New England Journal of Medicine. 1994; 331: 842-845
        • Gross V.
        • Andus T.
        • Caesar I.
        • et al.
        Oral pH-modified release budesonide versus 6-methylprednisolone in active Crohn’s disease. German/Austrian Budesonide Study Group.
        European Journal of Gastroenterology & Hepatology. 1996; 8: 905-909
        • Campieri M.
        • Ferguson A.
        • Doe W.
        • et al.
        Oral budesonide is as effective as oral prednisolone in active Crohn’s disease. The Global Budesonide Study Group.
        Gut. 1997; 41: 209-214
        • Bar-Meir S.
        • Chowers Y.
        • Lavy A.
        • et al.
        Budesonide versus prednisone in the treatment of active Crohn’s disease. The Israeli Budesonide Study Group.
        Gastroenterology. 1998; 115: 835-840
        • Escher J.C.
        • European Collaborative Research Group on Budesonide in Paediatric IBD
        Budesonide versus prednisolone for the treatment of active Crohn’s disease in children: a randomized, double-blind, controlled, multicentre trial.
        European Journal of Gastroenterology & Hepatology. 2004; 16: 47-54
        • Sandborn W.J.
        • Travis S.
        • Moro L.
        • et al.
        Once-daily budesonide MMX® extended-release tablets induce remission in patients with mild to moderate ulcerative colitis: results from the CORE I study.
        Gastroenterology. 2012; 143: 1218-1226
        • Travis S.P.
        • Danese S.
        • Kupcinskas L.
        • et al.
        Once-daily budesonide MMX in active, mild-to-moderate ulcerative colitis: results from the randomised CORE II study.
        Gut. 2014; 63: 433-441
        • Gross V.
        • Bunganic I.
        • Belousova E.A.
        • et al.
        3 g mesalazine granules are superior to 9 mg budesonide for achieving remission in active ulcerative colitis: a double-blind, double-dummy, randomised trial.
        Journal of Crohn’s and Colitis. 2011; 5: 129-138
        • Löfberg R.
        • Danielsson A.
        • Suhr O.
        • et al.
        Oral budesonide versus prednisolone in patients with active extensive and left-sided ulcerative colitis.
        Gastroenterology. 1996; 110: 1713-1718
        • Lichtenstein G.R.
        • Travis S.
        • Danese S.
        • et al.
        Budesonide MMX for the induction of remission of mild to moderate ulcerative colitis: a pooled safety analysis.
        Journal of Crohn’s and Colitis. 2015; 9: 738-746
        • Ford A.C.
        • Bernstein C.N.
        • Khan K.J.
        • et al.
        Glucocorticosteroid therapy in inflammatory bowel disease: systematic review and meta-analysis.
        American Journal of Gastroenterology. 2011; 106: 590-599
        • Rizzello F.
        • Gionchetti P.
        • D’Arienzo A.
        • et al.
        Oral beclometasone dipropionate in the treatment of active ulcerative colitis: a double-blind placebo-controlled study.
        Alimentary Pharmacology & Therapeutics. 2002; 16: 1109-1116
        • Van Assche G.
        • Manguso F.
        • Zibellini M.
        • et al.
        Oral prolonged release beclomethasone dipropionate and prednisone in the treatment of active ulcerative colitis: results from a double-blind, randomized, Parallel Group Study.
        American Journal of Gastroenterology. 2015; 110: 708-715
        • Greenberg G.R.
        • Feagan B.G.
        • Martin F.
        • et al.
        Oral budesonide as maintenance treatment for Crohn’s disease: a placebo-controlled, dose-ranging study. Canadian Inflammatory Bowel Disease Study Group.
        Gastroenterology. 1996; 110: 45-51
        • Löfberg R.
        • Rutgeerts P.
        • Malchow H.
        • et al.
        Budesonide prolongs time to relapse in ileal and ileocaecal Crohn’s disease. A placebo controlled one year study.
        Gut. 1996; 39: 82-86
        • Gross V.
        • Andus T.
        • Ecker K.W.
        • et al.
        Low dose oral pH modified release budesonide for maintenance of steroid induced remission in Crohn’s disease. The Budesonide Study Group.
        Gut. 1998; 42: 493-496
        • Hanauer S.
        • Sandborn W.J.
        • Persson A.
        • et al.
        Budesonide as maintenance treatment in Crohn’s disease: a placebo-controlled trial.
        Alimentary Pharmacology & Therapeutics. 2005; 21: 363-371
        • Kuenzig M.E.
        • Rezaie A.
        • Seow C.H.
        • et al.
        Budesonide for maintenance of remission in Crohn’s disease.
        Cochrane Database of Systematic Reviews. 2014; 21: CD002913
        • Hellers G.
        • Cortot A.
        • Jewell D.
        • et al.
        Oral budesonide for prevention of postsurgical recurrence in Crohn’s disease. The IOIBD Budesonide Study Group.
        Gastroenterology. 1999; 116: 294-300
        • Ewe K.
        • Böttger T.
        • Buhr H.J.
        • et al.
        Low-dose budesonide treatment for prevention of postoperative recurrence of Crohn’s disease: a multicentre randomized placebo-controlled trial. German Budesonide Study Group.
        European Journal of Gastroenterology & Hepatology. 1999; 11: 277-282
        • Schoon E.J.
        • Bollani S.
        • Mills P.R.
        • et al.
        Bone mineral density in relation to efficacy and side effects of budesonide and prednisolone in Crohn’s disease.
        Clinical Gastroenterology and Hepatology. 2005; 3: 113-121
        • Prantera C.
        • Rizzi M.
        • Cottone M.
        • et al.
        Beclomethasone dipropionate in Crohn’s ileitis: a randomised, double-blind trial.
        Digestive and Liver Disease. 2011; 43: 459-464
        • D’Haens G.
        • Verstraete A.
        • Cheyns K.
        • et al.
        Bone turnover during short-term therapy with methylprednisolone or budesonide in Crohn’s disease.
        Alimentary Pharmacology & Therapeutics. 1998; 12: 419-424
        • Cino M.
        • Greenberg G.R.
        Bone mineral density in Crohn’s disease: a longitudinal study of budesonide, prednisone, and nonsteroid therapy.
        American Journal of Gastroenterology. 2002; 97: 915-921
        • Lichtenstein G.R.
        • Bengtsson B.
        • Hapten-White L.
        • et al.
        Oral budesonide for maintenance of remission of Crohn’s disease: a pooled safety analysis.
        Alimentary Pharmacology & Therapeutics. 2009; 15: 643-653
        • Beaulieu D.B.
        • Ananthakrishnan A.N.
        • Issa M.
        • et al.
        Budesonide induction and maintenance therapy for Crohn’s disease during pregnancy.
        Inflammatory Bowel Diseases. 2009; 15: 25-28
        • Christensson C.
        • Thorén A.
        • Lindberg B.
        Safety of inhaled budesonide: clinical manifestations of systemic corticosteroid-related adverse effects.
        Drug Safety. 2008; 31: 965-988
        • de Aguiar M.M.
        • da Silva H.J.
        • Rizzo J.A.
        • et al.
        Inhaled beclomethasone in pregnant asthmatic women—a systematic review.
        Allergologia et Immunopathologia. 2014; 42: 493-499
        • Powrie R.O.
        • Larson L.
        • Miller M.
        Managing asthma in expectant mothers.
        Treatments in Respiratory Medicine. 2006; 5: 1-10
        • Nielsen O.H.
        • Maxwell C.
        • Hendel J.
        IBD medications during pregnancy and lactation.
        Nature Reviews Gastroenterology & Hepatology. 2014; 11: 116-127
        • Gionchetti P.
        • Dignass A.
        • Magro F.D.
        • et al.
        3rd European evidence-based consensus on the diagnosis and management of Crohn’s disease 2016: part 2: surgical management and special situations.
        Journal of Crohn’s Colitis. 2016; 11: 135-149
        • Van Assche G.
        • Dignass A.
        • Bokemeyer B.
        • et al.
        Second European evidence-based consensus on the diagnosis and management of ulcerative colitis: special situations.
        Journal of Crohn’s and Colitis. 2013; 7: 1-33
        • Segev S.
        • Yaniv I.
        • Haverstock D.
        • et al.
        Safety of long-term therapy with ciprofloxacin: data analysis of controlled clinical trials and review.
        Clinical Infectious Diseases. 1999; 28: 299-308
        • Owens R.
        • Ambrose P.
        Antimicrobial safety: focus on fluoroquinolones.
        Clinical Infectious Diseases. 2005; 41: S144-S157
        • Issa M.
        • Vijayapal A.
        • Graham M.B.
        • et al.
        Impact of Clostridium difficile on inflammatory bowel disease.
        Clinical Gastroenterology and Hepatology. 2007; 5: 345-351
        • Orman E.S.
        • Conjeevaram H.S.
        • Vuppalanchi R.
        • et al.
        Clinical and histopathological features of fluoroquinolone-induced liver injury.
        Clinical Gastroenterology and Hepatology. 2011; 9: 517-523
        • Tomé A.M.
        • Filipe A.
        Quinolones: review of psychiatric and neurological adverse reactions.
        Drug Safety. 2011; 34: 465-488
        • Melhus A.
        Fluoroquinolones and tendon disorders.
        Expert Opinion on Drug Safety. 2005; 4: 299-309
        • Adefurin A.
        • Sammons H.
        • Jacqz-Aigrain E.
        • et al.
        Ciprofloxacin safety in paediatrics: a systematic review.
        Archives of Disease in Childhood. 2011; 96: 874-880
        • Van der Linden P.D.
        • Sturkenboom M.C.
        • Herings R.M.
        • et al.
        Fluoroquinolones and risk of achilles tendon disorders: case-control study.
        BMJ. 2002; 324: 1306-1307
        • Arabyat R.M.
        • Raisch D.W.
        • McKoy J.M.
        • et al.
        Fluoroquinolone-associated tendon-rupture: a summary of reports in the Food and Drug Administration’s adverse event reporting system.
        Expert Opinion on Drug Safety. 2015; 14: 1653-1660
        • Prabhakar M.
        • Khran A.D.
        Ciprofloxacin-induced acquired long QT syndrome.
        Heart Rhythm. 2004; 1: 624-626
        • Rutgeerts P.
        • Hiele M.
        • Geboes K.
        • et al.
        Controlled trial of metronidazole treatment for prevention of Crohn’s recurrence after ileal resection.
        Gastroenterology. 1995; 108: 1617-1621
        • Karamanakos P.N.
        • Pappas P.
        • Boumba V.A.
        • et al.
        Pharmaceutical agents known to produce disulfiram-like reaction: effects on hepatic ethanol metabolism and brain monoamines.
        International Journal of Toxicology. 2007; 26: 423-432
        • Smith J.A.
        Neutropenia associated with metronidazole therapy.
        Canadian Medical Association Journal. 1980; 123: 202
        • Kuriyama A.
        • Jackson J.L.
        • Doi A.
        • et al.
        Metronidazole-induced central nervous system toxicity: a systematic review.
        Clinical Neuropharmacology. 2011; 34: 241-247
        • Bernstein L.H.
        • Frank M.S.
        • Brandt L.J.
        • et al.
        Healing of perianal Crohn’s disease with metronidazole.
        Gastroenterology. 1980; 79: 357-365
        • Jacobovits J.
        • Schuster M.M.
        Metronidazole therapy for Crohn’s disease and associated fistulae.
        American Journal of Gastroenterology. 1984; 79: 533-540
        • Gillis J.C.
        • Brogden R.N.
        Rifaximin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic potential in conditions mediated by gastrointestinal bacteria.
        Drugs. 1995; 49: 467-484
        • Scarpignato C.
        • Pelosini I.
        Rifaximin, a poorly absorbed antibiotic: pharmacology and clinical potential.
        Chemotherapy. 2005; 51: 36-66
        • Berkovitch M.
        • Pastuszak A.
        • Gazarian M.
        • et al.
        Safety of the new quinolones in pregnancy.
        Obstetrics & Gynecology. 1994; 84: 535-538
        • Loebstein R.
        • Addis A.
        • Ho E.
        • et al.
        Pregnancy outcome following gestational exposure to fluoroquinolones: a multicenter prospective controlled study.
        Antimicrobial Agents and Chemotherapy. 1998; 42: 1336-1339
        • van der Woude C.J.
        • Ardizzone S.
        • Bengtson M.B.
        • et al.
        The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease.
        Journal of Crohn’s and Colitis. 2015; 9: 107-124
        • Mahadevan U.
        • Kane S.
        American Gastroenterological Association institute technical review on the use of gastrointestinal medications in pregnancy.
        Gastroenterology. 2006; 131: 283-311
        • Czeizel A.E.
        • Rockenbauer M.
        A population based case-control teratologic study of oral metronidazole treatment during pregnancy.
        British Journal of Obstetrics and Gynaecology. 1998; 105: 322-327
        • Burtin P.
        • Taddio A.
        • Ariburnu O.
        • et al.
        Safety of metronidazole in pregnancy: a meta-analysis.
        American Journal of Obstetrics & Gynecology. 1995; 172: 525-529
        • Caro-Paton T.
        • Carvajal A.
        • Martin de Diego I.
        • et al.
        Is metronidazole teratogenic? A meta-analysis.
        British Journal of Clinical Pharmacology. 1997; 44: 179-182
        • Koss C.A.
        • Baras D.C.
        • Lane S.D.
        • et al.
        Investigation of metronidazole use during pregnancy and adverse birth outcomes.
        Antimicrobial Agents and Chemotherapy. 2012; 56: 4800-4805
        • Mathew J.L.
        Effect of maternal antibiotics on breast feeding infants.
        Postgraduate Medical Journal. 2004; 80: 196-200
        • Chaparro M.
        Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients.
        Inflammatory Bowel Diseases. 2013; 19: 1404-1410
        • Saibeni S.
        • Virgilio T.
        • D’Incà R.
        • et al.
        The use of thiopurines for the treatment of inflammatory bowel diseases in clinical practice.
        Digestive and Liver Disease. 2008; 40: 814-820
        • Jharap B.
        • Seinen M.L.
        • de Boer N.K.
        • et al.
        Thiopurine therapy in inflammatory bowel disease patients: analyses of two 8-year intercept cohorts.
        Inflammatory Bowel Diseases. 2010; 16: 1541-1549
        • Costantino G.
        • Furfaro F.
        • Belvedere A.
        • et al.
        Thiopurine treatment in inflammatory bowel disease: response predictors, safety, and withdrawal in follow-up.
        Journal of Crohn’s and Colitis. 2012; 6: 588-596
        • Kim P.S.
        • Zlatanic J.
        • Korelitz B.I.
        • et al.
        Optimum duration of treatment with 6-mercaptopurine for Crohn’s disease.
        American Journal of Gastroenterology. 1999; 94: 3254-3257
        • Bidinger J.J.
        • Sky K.
        • Battafarano D.F.
        • et al.
        The cutaneous and systemic manifestations of azathioprine hypersensitivity syndrome.
        Journal of the American Academy of Dermatology. 2011; 65: 184-191
        • Lewis J.D.
        • Abramson O.
        • Pascua M.
        • et al.
        Timing of myelosuppression during thiopurine therapy for inflammatory bowel disease: implications for monitoring recommendations.
        Clinical Gastroenterology and Hepatology. 2009; 7: 1195-1201
        • Gisbert J.P.
        • Gomollón F.
        Thiopurine-induced myelotoxicity in patients with inflammatory bowel disease: a review.
        American Journal of Gastroenterology. 2008; 103: 1783-1800
        • Lennard L.
        The clinical pharmacology of 6-mercaptopurine.
        European Journal of Clinical Pharmacology. 1992; 43: 329-339
        • Dubinsky M.C.
        • Yang H.
        • Hassard P.V.
        • et al.
        6-MP metabolite profiles provide a biochemical explanation for 6-MP resistance in patients with inflammatory bowel disease.
        Gastroenterology. 2002; 122: 904-915
        • Lennard L.
        • Lilleyman J.S.
        • Van Loon J.
        • et al.
        Genetic variation in response to 6-mercaptopurine for childhood acute lymphoblastic leukemia.
        Lancet. 1990; 336: 225-229
        • Gisbert J.P.
        • Niño P.
        • Rodrigo L.
        • et al.
        Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients.
        American Journal of Gastroenterology. 2006; 101: 2769-2776
        • Dubinsky M.C.
        • Lamothe S.
        • Yang H.Y.
        • et al.
        Pharmacogenomics and metabolite measurement for 6-mercaptopurine therapy in inflammatory bowel disease.
        Gastroenterology. 2000; 118: 705-713
        • Cuffari C.
        • Theorêt Y.
        • Latour S.
        • et al.
        6-Mercaptopurine metabolism in Crohn’s disease: correlation with efficacy and toxicity.
        Gut. 1996; 39: 401-406
        • Roblin X.
        • Peyrin-Biroulet L.
        • Phelip J.M.
        • et al.
        A 6-thioguanine nucleotide threshold level of 400 pmol/8 × 10(8) erythrocytes predicts azathioprine refractoriness in patients with inflammatory bowel disease and normal TPMT activity.
        American Journal of Gastroenterology. 2008; 103: 3115-3122
        • Dubinsky M.C.
        • Reyes E.
        • Ofman J.
        • et al.
        A cost-effectiveness analysis of alternative disease management strategies in patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine.
        American Journal of Gastroenterology. 2005; 100: 2239-2247
        • Gisbert J.P.
        • Niño P.
        • Rodrigo L.
        • et al.
        Thiopurine methyltransferase (TPMT) activity and adverse effects of azathioprine in inflammatory bowel disease: long-term follow-up study of 394 patients.
        American Journal of Gastroenterology. 2006; 101: 2769-2776
        • Relling M.V.
        • Gardner E.E.
        • Sandborn W.J.
        • et al.
        Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing.
        Clinical Pharmacology & Therapeutics. 2011; 89: 387-391
        • Zur R.M.
        • Roy L.M.
        • Ito S.
        • et al.
        Thiopurine S-methyltransferase testing for averting drug toxicity: a meta-analysis of diagnostic test accuracy.
        Pharmacogenomics Journals. 2016; 17: 633-656
        • Palmieri O.
        • Latiano A.
        • Bossa F.
        • et al.
        Sequential evaluation of thiopurine methyltransferase, inosine triphosphate pyrophosphatase, and HPRT1 genes polymorphisms to explain thiopurines’ toxicity and efficacy.
        Alimentary Pharmacology & Therapeutics. 2007; 26: 737-745
        • Winter J.
        • Walker A.
        • Shapiro D.
        • et al.
        Cost-effectiveness of thiopurine methyltransferase genotype screening in patients about to commence azathioprine therapy for treatment of inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2004; 20: 593-599
        • Van den Akkervan Marle M.E.
        • Gurwitz D.
        • Detmar S.B.
        • et al.
        Cost-effectiveness of pharmacogenomics in clinical practice: a case study of thiopurine methyltransferase genotyping in acute lymphoblastic leukaemia in Europe.
        Pharmacogenomics. 2006; 7: 783-792
        • Compagni A.
        • Bartoli S.
        • Buehrlen B.
        • et al.
        Avoiding adverse drug reactions by pharmacogenetic testing: a systematic review of the economic evidence in the case of TPMT and AZA-induced side effects.
        International Journal of Technology Assessment in Health Care. 2008; 24: 294-302
        • Preist V.L.
        • Begg E.J.
        • Gardiner S.J.
        • et al.
        Pharmacoeconomic analyses of azathioprine methotrexate and prospective pharmacogenetic testing for the management of inflammatory bowel disease.
        Pharmacoeconomics. 2006; 24: 761-781
        • Sayani F.A.
        • Prosser C.
        • Bailey R.J.
        • et al.
        Thiopurine methyltransferase enzyme activity determination before treatment of inflammatory bowel disease with azathioprine: effect on cost and adverse events.
        Canadian Journal of Gastroenterology. 2005; 19: 147-151
        • Bermejo F.
        • López-Sanromán A.
        • Algaba A.
        • et al.
        Mercaptopurine rescue after azathioprine-induced liver injury in inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2010; 31: 120-124
        • Kiefer K.
        • El-Matary W.
        6-Mercaptopurine as an alternative to azathioprine in azathioprine-induced hepatoxicity.
        Inflammatory Bowel Diseases. 2009; 15: 318-319
        • Kennedy N.A.
        • Rhatigan E.
        • ArnoltI D.
        • et al.
        A trial of mercaptopurine is a safe strategy in patients with inflammatory bowel disease intolerant to azathioprine: an observational study, systematic review and meta-analysis.
        Alimentary Pharmacology & Therapeutics. 2013; 38: 1255-1266
        • Tuyama A.C.
        • Karakauer M.
        • Alzaabi M.
        • et al.
        Mercaptopurine induced hepatoportal sclerosis in a patient with Crohn’s Disease.
        Journal of Crohn’s and Colitis. 2013; 7: 590-593
        • Konidari A.
        • Matary W.E.
        Use of thiopurines in inflammatory bowel disease: safety issues.
        World Journal of Gastrointestinal Pharmacology and Therapeutics. 2014; 5: 63-76
        • Sansone S.
        • Guarino M.
        • Castiglione F.
        • et al.
        Hepatitis B and C virus reactivation in immunosuppressed patients with inflammatory bowel disease.
        World Journal of Gastroenterology. 2014; 20: 3516-3524
        • Dewit O.
        • Vanheuverzwyn R.
        • Desager J.P.
        • et al.
        Interaction between azathioprine and aminosalicylates: an in vivo study in patients with Crohn’s disease.
        Alimentary Pharmacology & Therapeutics. 2002; 16: 79-85
        • Daperno M.
        • Sostegni R.
        • Canaparo R.
        • et al.
        Prospective study of the effects of concomitant medications on thiopurine metabolism in inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2009; 30: 843-853
        • Ansari A.
        • Patel N.
        • Sanderson J.
        • et al.
        Low-dose azathioprine or mercaptopurine in combination with allopurinol can bypass many adverse drug reactions in patients with inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2010; 31: 640-647
        • Govani S.M.
        • Higgins P.D.
        Combination of thiopurines and allopurinol: adverse events and clinical benefit in IBD.
        Journal of Crohn’s and Colitis. 2010; 4: 444-449
        • Vögelin M.
        • Biedermann L.
        • Frei P.
        • et al.
        The impact of azathioprine-associated lymphopenia on the onset of opportunistic infections in patients with inflammatory bowel disease.
        PLoS One. 2016; 11: e0155218
        • Teksik P.
        • Cosnes J.
        • Sokol H.
        • et al.
        Incidence of benign upper respiratory tract infections, HSV and HPV cutaneous infections in inflammatory bowel disease patients treated with azathioprine.
        Alimentary Pharmacology & Therapeutics. 2009; 29: 1106-1113
        • James D.G.
        • Stone C.D.
        • Wang H.L.
        • et al.
        Reactive hemophagocytic syndrome complicating the treatment of inflammatory bowel disease.
        Inflammatory Bowel Diseases. 2006; 12: 573-580
        • Connell W.R.
        • Kamm M.A.
        • Dickson M.
        • et al.
        Long-term neoplasia risk after azathioprine treatment in Inflammatory Bowel Disease.
        Lancet. 1994; 343: 1249-1252
        • Glick S.N.
        • Teplick S.K.
        • Goodman L.R.
        • et al.
        Development of lymphoma in patients with Crohn’s disease.
        Radiology. 1984; 153: 337-339
        • Khan N.
        • Abbas A.M.
        • Lichtenstein G.R.
        • et al.
        Risk of lymphoma in patients with ulcerative colitis treated with thiopurines: a nationwide retrospective cohort study.
        Gastroenterology. 2013; 145: 1007-1015
        • Lakatos P.L.
        • Lovasz B.D.
        • David G.
        • et al.
        The risk of lymphoma and immunomodulators in patients with inflammatory bowel diseases: results from a population-based cohort in Eastern Europe.
        Journal of Crohn’s and Colitis. 2013; 7: 385-391
        • Lewis J.
        • Schwartz S.
        • Lichtenstein G.R.
        Azathioprine for maintenance of remission in Crohn’s disease: benefits outweigh the risk of lymphoma.
        Gastroenterology. 2000; 118: 1018-1024
        • Dayharsh G.
        • Loftus E.V.
        • Sandborn W.J.
        • et al.
        Epstein-Barr virus-positive lymphoma in patients with inflammatory bowel disease treated with azathioprine and 6-mercaptopurine.
        Gastroenterology. 2002; 122: 72-77
        • Kandiel A.
        • Fraser A.G.
        • Korelitz B.I.
        • et al.
        Increased risk of lymphoma among inflammatory bowel disease patients treated with azathioprine and 6-mercaptopurine.
        Gut. 2005; 54: 1121-1125
        • Beaugerie L.
        • Brousse N.
        • Bouvier A.M.
        • et al.
        Lymphoproliferative disorders in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
        Lancet. 2009; 374: 1617-1625
        • Vos A.C.
        • Bakkal N.
        • Minnee R.C.
        • et al.
        Risk of malignant lymphoma in patients with inflammatory bowel diseases: a Dutch nationwide study.
        Inflammatory Bowel Diseases. 2011; 17: 1837-1845
        • Long M.D.
        • Herfarth H.H.
        • Pipkin C.A.
        • et al.
        Increased risk for non-melanoma skin cancer in patients with inflammatory bowel disease.
        Clinical Gastroenterology and Hepatology. 2010; 8: 268-274
        • Setshedi M.
        • Epstein D.
        • Winter T.A.
        • et al.
        Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study.
        Journal of Gastroenterology and Hepatology. 2012; 27: 385-389
        • Long M.D.
        • Kappelman M.D.
        • Pipkin C.A.
        Nonmelanoma skin cancer in inflammatory bowel disease: a review.
        Inflammatory Bowel Diseases. 2011; 17: 1423-1427
        • Peyrin-Biroulet L.
        • Khosrotehrani K.
        • Carrat F.
        • et al.
        Increased risk for nonmelanoma skin cancers in patients who receive thiopurines for inflammatory bowel disease.
        Gastroenterology. 2011; 141: 1621-1628
        • Ariyaratnam J.
        • Subramanian V.
        Association between thiopurine use and nonmelanoma skin cancers in patients with inflammatory bowel disease: a meta-analysis.
        American Journal of Gastroenterology. 2014; 109: 163-169
        • Bourrier A.
        • Carrat F.
        • Colombel J.F.
        • et al.
        Excess risk of urinary tract cancers in patients receiving thiopurines for inflammatory bowel disease: a prospective observational cohort study.
        Alimentary Pharmacology & Therapeutics. 2016; 43: 252-261
        • Colombel J.F.
        • Loftus Jr., E.V.
        • Tremaine W.J.
        • et al.
        Early postoperative complications are not increased in patients with Crohn’s disease treated perioperatively with infliximab or immunosuppressive therapy.
        American Journal of Gastroenterology. 2004; 99: 878-883
        • Mahadevan U.
        • Loftus Jr., E.V.
        • Tremaine W.J.
        • et al.
        Azathioprine or 6-mercaptopurine before colectomy for ulcerative colitis is not associated with increased postoperative complications.
        Inflammatory Bowel Diseases. 2002; 8: 311-316
        • Damas O.M.
        • Deshpande A.R.
        • Avalos D.J.
        • et al.
        Treating inflammatory bowel disease in pregnancy: the issues we face today.
        Journal of Crohn’s and Colitis. 2015; 9: 928-936
        • Kwan L.Y.
        • Mahadevan U.
        Inflammatory bowel disease and pregnancy: an update.
        Expert Review of Clinical Immunology. 2010; 6: 643-657
        • Casanova M.J.
        • Chaparro M.
        • Domènech E.
        • et al.
        Safety of thiopurines and anti-TNF-á drugs during pregnancy in patients with inflammatory bowel disease.
        American Journal of Gastroenterology. 2013; 108: 433-440
        • Caprilli R.
        • Angelucci E.
        • Cocco A.
        • et al.
        Appropriateness of immunosuppressive drugs in inflammatory bowel diseases assessed by RAND method: Italian Group for IBD (IG-IBD) position statement.
        Digestive and Liver Disease. 2005; 37: 407-417
        • Jharap B.
        • de Boer N.K.
        • Stokkers P.
        • et al.
        Intrauterine exposure and pharmacology of conventional thiopurine therapy in pregnant patients with inflammatory bowel disease.
        Gut. 2014; 63: 451-457
        • Teruel C.
        • López-San Román A.
        • Bermejo F.
        • et al.
        Outcomes of pregnancies fathered by inflammatory bowel disease patients exposed to thiopurines.
        American Journal of Gastroenterology. 2010; 105: 2003-2008
        • Rajapakse R.O.
        • Korelitz B.I.
        • Zlatanic J.
        • et al.
        Outcome of pregnancies when fathers are treated with 6-mercaptopurine for inflammatory bowel disease.
        American Journal of Gastroenterology. 2000; 95: 648-684
        • Akbari M.
        • Shah S.
        • Velayos F.S.
        • et al.
        Systematic review and meta-analysis on the effects of thiopurines on birth outcomes from female and male patients with inflammatory bowel disease.
        Inflammatory Bowel Diseases. 2013; 19: 15-22
        • Feagan B.G.
        • Rochon J.
        • Fedorak R.N.
        • et al.
        Methotrexate for the treatment of Crohn’s disease. The North American Crohn’s Study Group Investigators.
        The New England Journal of Medicine. 1995; 332: 292-297
        • Shea B.
        • Swinden M.V.
        • Tanjong Ghogomu E.
        • et al.
        Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis.
        Cochrane Database of Systematic Reviews. 2013; 5: CD000951
        • Malatjalian D.A.
        • Ross J.B.
        • Williams C.N.
        • et al.
        Methotrexate hepatotoxicity in psoriatics: report of 104 patients from Nova Scotia, with analysis of risks from obesity, diabetes and alcohol consumption during long term follow-up.
        Canadian Journal of Gastroenterology. 1996; 10: 369-375
        • Lewis J.H.
        • Schiff E.
        Methotrexate-induced chronic liver injury: guidelines for detection and prevention. The ACG Committee on FDA-related matters. American College of Gastroenterology.
        American Journal of Gastroenterology. 1988; 83: 1337-1345
        • Suares N.C.
        • Hamlin P.J.
        • Greer D.P.
        • et al.
        Efficacy and tolerability of methotrexate therapy for refractory Crohn’s disease: a large single-centre experience.
        Alimentary Pharmacology & Therapeutics. 2012; 35: 284-291
        • Cummings J.R.
        • Herrlinger K.R.
        • Travis S.P.
        • et al.
        Oral methotrexate in ulcerative colitis.
        Alimentary Pharmacology & Therapeutics. 2005; 21: 385-389
        • Chande N.
        • Abdelgadir I.
        • Gregor J.
        The safety and tolerability of methotrexate for treating patients with Crohn’s disease.
        Journal of Clinical Gastroenterology. 2011; 45: 599-601
        • Khan N.
        • Abbas A.M.
        • Whang N.
        • et al.
        Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials.
        Inflammatory Bowel Diseases. 2012; 18: 359-367
        • Lemann M.
        • Zenjari T.
        • Bouhnik Y.
        • et al.
        Methotrexate in Crohn’s disease: long-term efficacy and toxicity.
        American Journal of Gastroenterology. 2000; 95: 1730-1734
        • Te H.S.
        • Schiano T.D.
        • Kuan S.F.
        • et al.
        Hepatic effects of long-term methotrexate use in the treatment of inflammatory bowel disease.
        American Journal of Gastroenterology. 2000; 95: 3150-3156
        • Watanabe K.
        • Takase K.
        • Ohno S.
        • et al.
        Reactivation of hepatitis B virus in a hepatitis B surface antigen-negative patient with rheumatoid arthritis treated with methotrexate.
        Modern Rheumatology. 2012; 22: 470-473
        • Barbero-Villares A.
        • Mendoza Jimenez-Ridruejo J.
        • Taxonera C.
        • et al.
        Evaluation of liver fibrosis by transient elastography (Fibroscan(R)) in patients with inflammatory bowel disease treated with methotrexate: a multicentric trial.
        Scandinavian Journal of Gastroenterology. 2012; 47: 575-579
        • Kremer J.M.
        • Alarcon G.S.
        • Lightfoot Jr., R.W.
        • et al.
        Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology.
        Arthritis & Rheumatology. 1994; 37: 316-328
        • Powell H.R.
        • Ekert H.
        Methotrexate-induced congenital malformations.
        Medical Journal of Australia. 1971; 2: 1076-1077
        • Saibeni S.
        • Bollani S.
        • Losco A.
        • et al.
        The use of methotrexate for treatment of inflammatory bowel disease in clinical practice.
        Digestive and Liver Disease. 2012; 44: 123-127
        • Sandborn W.J.
        A critical review of cyclosporine therapy in inflammatory bowel disease.
        Inflammatory Bowel Diseases. 1995; 1: 48-63
        • Lichtiger S.
        • Present D.H.
        • Kornbluth A.
        • et al.
        Cyclosporine in severe ulcerative colitis refractory to steroid therapy.
        New England Journal of Medicine. 1994; 330: 1841-1845
        • Rahier J.F.
        • Ben-Horin S.
        • Chowers Y.
        • et al.
        European evidence-based Consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease.
        Journal of Crohn’s and Colitis. 2009; 3: 47-91
        • Campbell S.
        • Travis S.
        • Jewell D.
        Cyclosporin use in acute ulcerative colitis: a long-term experience.
        European Journal of Gastroenterology & Hepatology. 2005; 17: 79-84
        • Dantal J.
        • Pohanka E.
        Malignancies in renal transplantation: an unmet medical need.
        Nephrology Dialysis Transplantation. 2007; 22: i4-i10
        • Muellenhoff M.W.
        • Koo J.Y.
        Cyclosporine and skin cancer: an international dermatologic perspective over 25 years of experience. A comprehensive review and pursuit to define safe use of cyclosporine in dermatology.
        Journal of Dermatological Treatment. 2012; 23: 290-304
        • Beyaert R.
        • Beaugerie L.
        • Van Assche G.
        • et al.
        Cancer risk in immune-mediated inflammatory diseases (IMID).
        Molecular Cancer. 2013; 12: 98
        • Masunaga Y.
        • Ohno K.
        • Ogawa R.
        • et al.
        Meta-analysis of risk of malignancy with immunosuppressive drugs in inflammatory bowel disease.
        Annals of Pharmacotherapy. 2007; 41: 21-28
        • Euvrard S.
        • Kanitakis J.
        • Claudy A.
        Skin cancers after organ transplantation.
        New England Journal of Medicine. 2003; 348: 1681-1691
        • Moloney F.J.
        • Comber H.
        • O’Lorcain P.
        • et al.
        A population-based study of skin cancer incidence and prevalence in renal transplant recipients.
        British Journal of Dermatology. 2006; 154: 498-504
        • Dantal J.
        • Hourmant M.
        • Cantarovich D.
        • et al.
        Effect of long-term immunosuppression in kidney-graft recipients on cancer incidence: randomized comparison of two cyclosporin regimens.
        Lancet. 1998; 351: 623-628
        • Hyde G.M.
        • Jewell D.P.
        • Kettlewell M.G.
        • et al.
        Cyclosporin for severe ulcerative colitis does not increase the rate of perioperative complications.
        Diseases of the Colon & Rectum. 2001; 44: 1436-1440
        • Poritz L.S.
        • Rowe W.A.
        • Swenson B.R.
        • et al.
        Intravenous cyclosporine for the treatment of severe steroid refractory ulcerative colitis: what is the cost?.
        Diseases of the Colon & Rectum. 2005; 48: 1685-1690
        • Costa M.L.
        • Surita F.G.
        • Passini R.
        • et al.
        Pregnancy outcome in female liver transplant recipients.
        Transplant Immunology. 2011; 43: 1337-1339
        • Millsop J.W.
        • Heller M.M.
        • Eliason M.J.
        • et al.
        Dermatological medication effects on male fertility.
        Dermatologic Therapy. 2013; 26: 337-346
        • Gisbert J.P.
        Safety of immunomodulators and biologics for the treatment of inflammatory bowel disease during pregnancy and breast-feeding.
        Inflammatory Bowel Diseases. 2010; 16: 881-895
        • Perales-Puchalt A.
        • Vila Vives J.M.
        • Lopez Montes J.
        • et al.
        Pregnancy outcomes after kidney transplantation—immunosuppressive therapy comparison.
        Maternal-Fetal and Neonatal Medicine. 2012; 25: 1363-1366
        • Branche J.
        • Cortot A.
        • Bourreille A.
        • et al.
        Cyclosporine treatment of steroid-refractory ulcerative colitis during pregnancy.
        Inflammatory Bowel Diseases. 2009; 15: 1044-1048
        • Lichtenstein L.
        • Ron Y.
        • Kivity S.
        • et al.
        Infliximab-related infusion reactions: systematic review.
        Journal of Crohn’s and Colitis. 2015; 9: 806-815
        • Hanauer S.B.
        • Feagan B.G.
        • Lichtenstein G.R.
        • et al.
        Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial.
        Lancet. 2002; 359: 1541-1549
        • Sands B.E.
        • Anderson F.H.
        • Bernstein C.N.
        • et al.
        Infliximab maintenance therapy for fistulizing Crohn’s disease.
        New England Journal of Medicine. 2004; 350: 876-885
        • Colombel J.F.
        • Loftus Jr., E.V.
        • Tremaine W.J.
        • et al.
        The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients.
        Gastroenterology. 2004; 126: 19-31
        • Lees C.W.
        • Ali A.I.
        • Thompson A.I.
        • et al.
        The safety profile of anti-tumour necrosis factor therapy in inflammatory bowel disease in clinical practice: analysis of 620 patient-years follow-up.
        Alimentary Pharmacology & Therapeutics. 2009; 29: 286-297
        • Cheifetz A.
        • Smedley M.
        • Martin S.
        • et al.
        The incidence and management of infusion reactions to infliximab: a large center experience.
        American Journal of Gastroenterology. 2003; 98: 1315-1324
        • Fidder H.
        • Schnitzler F.
        • Ferrante M.
        • et al.
        Long-term safety of infliximab for the treatment of inflammatory bowel disease: a single centre cohort study.
        Gut. 2009; 58: 501-508
        • Hanauer S.B.
        • Wagner C.L.
        • Bala M.
        • et al.
        Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn’s disease.
        Clinical Gastroenterology and Hepatology. 2004; 2: 542-553
        • Steenholdt C.
        • Svenson M.
        • Bendtzen K.
        • et al.
        Severe infusion reactions to infliximab: aetiology, immunogenicity and risk factors in patients with inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2011; 34: 51-58
        • Kugathasan S.
        • Levy M.B.
        • Saeian K.
        • et al.
        Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction.
        American Journal of Gastroenterology. 2002; 97: 1408-1414
        • Narula N.
        • Kainz S.
        • Petritsch W.
        • et al.
        The efficacy and safety of either infliximab or adalimumab in 362 patients with anti-TNF-α naïve Crohn’s disease.
        Alimentary Pharmacology & Therapeutics. 2016; 44: 170-180
        • Magro F.
        • Marques M.
        • Santos C.C.
        Episodic infliximab treatment induces infusion reactions.
        Inflammatory Bowel Diseases. 2008; 14: 1608-1610
        • Rutgeerts P.
        • Feagan B.G.
        • Lichtenstein G.R.
        • et al.
        Comparison of scheduled and episodic treatment strategies of infliximab in Crohn’s disease.
        Gastroenterology. 2004; 126: 402-413
        • O‘Meara S.
        • Nanda K.S.
        • Moss A.C.
        Antibodies to infliximab and risk of infusion reactions in patients with inflammatory bowel disease: a systematic review and meta-analysis.
        Inflammatory Bowel Diseases. 2014; 20: 1-6
        • Ainsworth M.A.
        • Bendtzen K.
        • Brynskov J.
        Tumor necrosis factor-alpha binding capacity and anti-Infliximab antibodies measured by fluid-phase radioimmunoassays as predictors of clinical efficacy of Infliximab in Crohn’s disease.
        American Journal of Gastroenterology. 2008; 103: 944-948
        • Cassinotti A.
        • Travis S.
        Incidence and clinical significance of immunogenicity to infliximab in Crohn’s disease: a critical systematic review.
        Inflammatory Bowel Diseases. 2009; 15: 1264-1275
        • Maggi E.
        • Vultaggio A.
        • Matucci A.
        Acute infusion reactions induced by monoclonal antibody therapy.
        Expert Review of Clinical Immunology. 2011; 7: 55-63
        • Ben-Horin S.
        • Mazor Y.
        • Yanai H.
        • et al.
        The decline of anti-drug antibody titres after discontinuation of anti-TNFs: implications for predicting re-induction outcome in IBD.
        Alimentary Pharmacology & Therapeutics. 2012; 35: 714-722
        • Vermeire S.
        • Noman M.
        • Van Assche G.
        • et al.
        Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease.
        Gut. 2007; 56: 1226-1231
        • Neef H.C.
        • Riebschleger M.P.
        • Adler J.
        Meta-analysis: rapid infliximab infusions are safe.
        Alimentary Pharmacology & Therapeutics. 2013; 38: 365-376
        • Farrell R.J.
        • Alsahli M.
        • Jeen Y.T.
        • et al.
        Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn’s disease: a randomized controlled trial.
        Gastroenterology. 2003; 124: 917-924
        • Jacobstein D.A.
        • Markowitz J.E.
        • Kirschner B.S.
        • et al.
        Premedication and infusion reactions with infliximab: results from a pediatric inflammatory bowel disease consortium.
        Inflammatory Bowel Diseases. 2005; 11: 442-446
        • Sandborn W.J.
        • Hanauer S.B.
        • Rutgeerts P.
        • et al.
        Adalimumab for maintenance treatment of Crohn’s disease: results of the CLASSIC II trial.
        Gut. 2007; 56: 1232-1239
        • Colombel J.F.
        • Sandborn W.J.
        • Rutgeerts P.
        • et al.
        Adalimumab for maintenance of clinical response and remission in patients with Crohn’s disease: the CHARM trial.
        Gastroenterology. 2007; 132: 52-65
        • Sandborn W.J.
        • Feagan B.G.
        • Marano C.
        • et al.
        Subcutaneous golimumab induces clinical response and remission in patients with moderate-to-severe ulcerative colitis.
        Gastroenterology. 2014; 146: 85-95
        • Sandborn W.J.
        • Feagan B.G.
        • Marano C.
        • et al.
        Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis.
        Gastroenterolog y. 2014; 146: 96-109
        • Mounach A.
        • Rezqi A.
        • Nouijai A.
        • et al.
        Stevens–Johnson syndrome complicating adalimumab therapy in rheumatoid arthritis disease.
        Rheumatology International. 2013; 33: 1351-1353
        • Marques I.
        • Lagos A.
        • Reis J.
        • et al.
        Reversible Henoch–Schönlein purpura complicating adalimumab therapy.
        Journal of Crohn’s and Colitis. 2012; 6: 796-799
        • Bonovas S.
        • Fiorino G.
        • Allocca M.
        • et al.
        Biologic therapies and risk of infection and malignancy in patients with inflammatory bowel disease: a systematic review and network meta-analysis.
        Clinical Gastroenterology and Hepatology. 2016; 14: 1385-1397
        • Danese S.
        • Gomollon F.
        • Governing Board and Operational Board of ECCO
        ECCO position statement: the use of biosimilar medicines in the treatment of inflammatory bowel disease (IBD).
        Journal of Crohn’s and Colitis. 2013; 7: 586-589
        • Danese S.
        • Fiorino G.
        • Michetti P.
        Changes in biosimilar knowledge among European Crohn’s Colitis Organization (ECCO) members: a updated survey.
        Journal of Crohn’s and Colitis. 2016; 10: 1362-1365
        • Gecse K.B.
        • Khanna R.
        • van den Brink G.R.
        • et al.
        Biosimilars in IBD: hope or expectation?.
        Gut. 2013; 62: 803-807
      3. AIFA. Position paper su farmaci biosimilari. http://www.agenziafarmaco.gov. 2228 it/it/content/position-paper-sui-farmaci-biosimilari-28052013 [Accessed 28 2229 May 2013]. 2230; 2013.

        • Annese V.
        • Vecchi M.
        Statements of the Italian Group for inflammatory bowel disease.
        Digestive and Liver Disease. 2014; 46: 963-968
        • Fiorino G.
        • Manetti N.
        • Armuzzi A.
        • et al.
        The PROSIT-BIO cohort: a prospective observational study of patients with inflammatory bowel disease treated with infliximab biosimilar.
        Inflammatory Bowel Diseases. 2017; 23: 233-243https://doi.org/10.1097/MIB.000000000000099
        • Scott F.I.
        • Lichtenstein G.R.
        Therapeutic drug monitoring of anti-TNF therapy in inflammatory bowel disease.
        Current Treatment Options in Gastroenterology. 2014; 12: 59-75
        • Baert F.
        • Noman M.
        • Vermeire S.
        • et al.
        Influence of immunogenicity on the long-term efficacy of infliximab in Crohn’s disease.
        New England Journal of Medicine. 2003; 348: 601-608
        • Kerbleski J.F.
        • Gottlieb A.B.
        Dermatological complications and safety of anti-TNF treatments.
        Gut. 2009; 58: 1033-1039
        • Schaible T.F.
        Long term safety of infliximab.
        Canadian Journal of Gastroenterology. 2000; 14: 29C-32C
        • Ramos-Casals M.
        • Brito-Zerón P.
        • Soto M.J.
        • et al.
        Autoimmune diseases induced by TNF-targeted therapies.
        Best Practice & Research Clinical Rheumatology. 2008; 22: 847-851
        • Yates V.M.
        • Watkinson G.
        • Kelman A.
        Further evidence for an association between psoriasis, Crohn’s disease and ulcerative colitis.
        British Journal of Dermatology. 1982; 106: 323-330
        • Ellinghaus D.
        • Ellinghaus E.
        • Nair R.P.
        • et al.
        Combined analysis of genome-wide association studies for Crohn disease and psoriasis identifies seven shared susceptibility loci.
        American Journal of Human Genetics. 2012; 90: 636-647
        • Cullen G.
        • Kroshinsky D.
        • Cheifetz A.S.
        • et al.
        Psoriasis associated with anti-tumour necrosis factor therapy in inflammatory bowel disease: a new series and a review of 120 cases from the literature.
        Alimentary Pharmacology & Therapeutics. 2011; 34: 1318-1327
        • Afzal A.
        • Wheat C.L.
        • Hu J.K.
        • et al.
        The association of psoriasiform rash with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease: a single academic center case series.
        Journal of Crohn’s and Colitis. 2014; 8: 480-488
        • Guerra I.
        • Algaba A.
        • Pérez-Calle J.L.
        • et al.
        Induction of psoriasis with anti-TNF agents in patients with inflammatory bowel disease: a report of 21 cases.
        Journal of Crohn’s and Colitis. 2012; 6: 518-523
        • Cleynen I.
        • Moerkercke W.V.
        • Billiet T.
        • et al.
        Characteristics of skin lesions associated with anti-tumor necrosis factor therapy in patients with inflammatory bowel disease: a cohort study.
        Annals of Internal Medicine. 2016; 164: 10-22
        • Fréling E.
        • Baumann C.
        • Cuny J.F.
        • et al.
        Cumulative incidence of, risk factors for, and outcome of dermatological complications of anti-TNF therapy in inflammatory bowel disease: a 14-year experience.
        American Journal of Gastroenterology. 2015; 110: 1186-1196
        • Passarini B.
        • Infusino S.D.
        • Barbieri E.
        • et al.
        Cutaneous manifestations in inflammatory bowel diseases: eight cases of psoriasis induced by anti-tumor-necrosis-factor antibody therapy.
        Dermatology. 2007; 215: 295-300
        • Mocci G.
        • Marzo M.
        • Papa A.
        • et al.
        Dermatological adverse reactions during anti-TNF treatments: focus on inflammatory bowel disease.
        Journal of Crohn’s and Colitis. 2013; 7: 769-779
        • Pugliese D.
        • Guidi L.
        • Ferraro P.M.
        • et al.
        Paradoxical psoriasis in a large cohort of patients with inflammatory bowel disease receiving treatment with anti-TNF alpha: 5-year follow-up study.
        Alimentary Pharmacology & Therapeutics. 2015; 42: 880-888
        • Harrison M.C.J.
        • Dixon W.G.
        • Watson K.D.
        • et al.
        BSRBR rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register.
        Annals of the Rheumatic Diseases. 2009; 68: 209-215
        • Baeten D.
        • Kruithof E.
        • Van den Bosch F.
        • et al.
        Systematic safety follow up in a cohort of 107 patients with spondyloarthropathy treated with infliximab: a new perspective on the role of host defence in the pathogenesis of the disease?.
        Rheumatic Diseases. 2003; 62: 829-834
        • Niess J.H.
        • Danese S.
        Anti-TNF and skin inflammation in IBD: a new paradox in gastroenterology?.
        Gut. 2014; 63: 533-535
        • Afzali A.
        • Wheat C.L.
        • Hu J.K.
        • et al.
        The association of psoriasiform rash with anti-tumor necrosis factor (anti-TNF) therapy in inflammatory bowel disease: a single academic center case series.
        Journal of Crohn’s and Colitis. 2014; 8: 480-488
        • Tillack C.
        • Ehmann L.M.
        • Friedrich M.
        • et al.
        Anti-TNF antibody-induced psoriasiform skin lesions in patients with inflammatory bowel disease are characterised by interferon-γ-expressing Th1 cells and IL-17 A/IL-22-expressing Th17 cells and respond to anti-IL-12/IL-23 antibody treatment.
        Gut. 2014; 63: 567-577
        • Moran G.W.
        • Lim A.W.
        • Bailey J.L.
        • et al.
        Review article: dermatological complications of immunosuppressive and anti-TNF therapy in inflammatory bowel disease.
        Alimentary Pharmacology & Therapeutics. 2013; 38: 1002-1024
        • Perdan-Pirkmajer K.
        • Hočevar A.
        • Rotar Ž.
        • et al.
        Tumour necrosis factor-alpha inhibitor-induced hepatic injury in patients with rheumatoid arthritis: two case reports and an analysis of the laboratory data from the Slovenian national biologicals registry.
        Rheumatology International. 2013; 33: 2885-2888
        • Rowe B.W.
        • Gala-Lopez B.
        • Tomlinson C.
        • et al.
        Fulminant hepatic failure necessitating transplantation following the initiation of infliximab therapy: a cautionary tale times two.
        Transplant International. 2013; 26: e110-e112
        • Di Minno M.N.
        • Iervolino S.
        • Peluso R.
        • et al.
        Hepatic steatosis and disease activity in subjects with psoriatic arthritis receiving tumor necrosis factor-α blockers.
        Journal of Rheumatology. 2012; 39: 1042-1046
        • Poulin Y.
        • Thérien G.
        Drug-induced hepatitis and lupus during infliximab treatment for psoriasis: case report and literature review.
        Journal of Cutaneous Medicine and Surgery. 2010; 14: 100-104
        • Coffin C.S.
        • Fraser H.F.
        • Panaccione R.
        • et al.
        Liver diseases associated with anti-tumor necrosis factor-alpha (TNF-α) use for inflammatory bowel disease.
        Inflammatory Bowel Diseases. 2011; 17: 479-484
        • Thomsen K.L.
        • Grønbæk H.
        • Dahlerup J.F.
        • et al.
        Prednisolone but not infliximab aggravates the upregulated hepatic nitrogen elimination in patients with active inflammatory bowel disease.
        Inflammatory Bowel Diseases. 2014; 20: 7-13
        • Bessissow T.
        • Renard M.
        • Hoffman I.
        • et al.
        Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy.
        Alimentary Pharmacology & Therapeutics. 2012; 36: 312-323
        • Sebastian S.
        • Ashton K.
        • Houston Y.
        • et al.
        Anti-TNF therapy induced immune neutropenia in Crohns disease—report of 2 cases and review of literature.
        Journal of Crohn’s and Colitis. 2012; 6: 713-716
        • Furst D.E.
        • Kay J.
        • Wasko M.C.
        • et al.
        The effect of golimumab on haemoglobin levels in patients with rheumatoid arthritis, psoriatic arthritis or ankylosing spondylitis.
        Rheumatology. 2013; 52: 1845-1855
        • Katsanos K.
        • Cavalier E.
        • Ferrante M.
        • et al.
        Intravenous iron therapy restores functional iron deficiency induced by infliximab.
        Journal of Crohn’s and Colitis. 2007; 1: 97-105