Portal de Periódicos da CAPES

Combination Biologic Therapy in Inflammatory Bowel Disease: Experience From a Tertiary Care Center

2020; Elsevier BV; Volume: 19; Issue: 3 Linguagem: Inglês

10.1016/j.cgh.2020.02.017

1542-7714

Lukasz Kwapisz, Laura E. Raffals, David H. Bruining, Darrell S. Pardi, William J. Tremaine, Sunanda V. Kane, Konstantinos A. Papadakis, Nayantara Coelho–Prabhu, John B. Kisiel, Valérie Heron, William A. Faubion, Edward V. Loftus,

Biosimilars and Bioanalytical Methods

The global incidence of inflammatory bowel disease (IBD) has increased considerably during the past few decades.1Kaplan G.G. Ng S.C. Understanding and preventing the global increase of inflammatory bowel disease.Gastroenterology. 2016; 52: 313-321.e2Google Scholar IBDs, composed of Crohn's disease (CD) and ulcerative colitis (UC), are characterized by heterogeneous presentation and widely variable clinical course. The therapeutic goals are to induce and maintain remission. Despite the current treatments available, many patients do not achieve this goal. Biologic agents are now commonly used earlier in the disease course, but they only result in 1-year remission rates of approximately 40% in selected IBD populations.2Hirten R.P. Iacucci M. Shah S. et al.Combining biologics in inflammatory bowel disease and other mediated inflammatory disorders.Clin Gastroenterol Hepatol. 2018; 16: 1374-1384Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar During the past 10 years, new biologic agents with different targeted molecular pathways have been introduced to strengthen the medical armamentarium in IBD.3Hindryckx P. Vande Casteele N. Novak G. et al.The expanding therapeutic armamentarium for inflammatory bowel disease: how to choose the right drug(s) for our patients?.J Crohns Colitis. 2018; 12: 105-119Crossref PubMed Scopus (42) Google Scholar As these new and diverse biologic agents have become available, many new questions have arisen,4Palmela C. Torres J. Cravo M. New trends in inflammatory bowel disease.GE Port J Gastroenterol. 2015; 22: 103-111Crossref PubMed Scopus (14) Google Scholar including whether multiple biologics can be combined to maximize efficacy while also limiting side effects in patients with incomplete response to standard therapeutic approaches. There has since been a paucity of data on combination biologic therapy in IBD patients, with a total of 5 case reports or series totaling 16 patients who were treated with combination biologics.2Hirten R.P. Iacucci M. Shah S. et al.Combining biologics in inflammatory bowel disease and other mediated inflammatory disorders.Clin Gastroenterol Hepatol. 2018; 16: 1374-1384Abstract Full Text Full Text PDF PubMed Scopus (50) Google Scholar,5Hirten R. Longman R.S. Bosworth B.P. et al.Vedolizumab and infliximab combination therapy in the treatment of Crohn's disease.Am J Gastroenterol. 2015; 110: 1737-1738Crossref PubMed Scopus (31) Google Scholar, 6Yzet C. Dupas J.L. Fumery M. Ustekinumab and anti-TNF combination therapy in patients with inflammatory bowel disease.Am J Gastroenterol. 2016; 111: 748-749Crossref PubMed Scopus (25) Google Scholar, 7Buer L.C.T. Hoivik M.L. Warren D.J. et al.Combining anti-TNF and vedolizumab in the treatment of inflammatory bowel disease: a case series.Inflamm Bowel Dis. 2018; 24: 997-1004Crossref PubMed Scopus (20) Google Scholar We therefore sought to summarize the efficacy and safety of combination biologic therapy in clinical practice at our tertiary medical center. This was a medical record–based, retrospective study of established CD or UC patients who were treated with infliximab, adalimumab, certolizumab pegol, golimumab, vedolizumab, or ustekinumab in combination at Mayo Clinic in Rochester, Minnesota. Indication for combination therapy was worsening luminal disease, and all patients were naive to the second biologic added. We analyzed each patient for disease characteristics, concomitant medications, clinical response, adverse events, and duration of follow-up. We also assessed imaging modalities, hospitalizations, surgeries, and laboratory investigations. We assessed healing patterns observed clinically, endoscopically, or histologically. We classified patients as refractory, responding, or in remission on the basis of those 3 clinical assessments. Clinical response was assessed by using the Crohn's disease-patient reported outcome signs and symptoms (CD-PRO/SS).8Higgins P.D.R. Harding G. Leidy N.K. et al.Development and validation of the Crohn's disease patient-reported outcomes signs and symptoms (CD-PRO/SS) diary.J Patient Rep Outcomes. 2017; 2: 24Crossref PubMed Scopus (12) Google Scholar Two factors were analyzed: (1) Bowel Signs and Symptoms, which included number of bowel movements (BMs), BMs mostly or completely liquid, and urge to have BMs right away; and (2) Abdominal Symptoms, which included pain in belly, bloating, and passing gas. For UC, the partial Mayo score was used to assess clinical response. Treatment-related adverse events were assessed throughout the duration of combined therapy. A total of 15 patients who were treated with combination biologics were identified (14 CD, 1 UC). Clinical features and outcomes are summarized in Table 1. Eight patients were treated with vedolizumab and an anti–tumor necrosis factor (TNF) agent. Two patients received ustekinumab with an anti-TNF agent, and 5 patients received vedolizumab with ustekinumab. Patients were followed for a median of 24 months (range, 6–72), and the median duration of combined biologic treatment was 6 months (range, 2–48). Eleven patients (73%) reported symptomatic improvement, 10 patients (67%) had reduction of corticosteroid use, and 4 patients (44%) had endoscopic or radiographic improvement. Four patients (27%) had infections requiring antibiotics, 3 patients were hospitalized, and 3 patients (20%) required surgical intervention. One patient discontinued one biologic because of arthralgias.Table 1Patient Characteristics and Clinical Outcomes in Combination Biologic TherapyPatient characteristics (14 CD and 1 UC)n = 15Clinical responseSurgery neededReduction in corticosteroidsHospitalizationInfectionAge, y, median36Sex, female, n (%)10 (66.7)Duration of IBD, y, median (range)12.5 (5–31)Prior biologics used, median (range)4 (1–7)History of penetrating disease, n (%)13 (86.7)History of perianal disease, n (%)8 (53.3)Baseline corticosteroids, n (%)13 (86.7)Baseline immunomodulator, n (%)4 (26.7)Anti-TNF with vedolizumab, n (%)8 (53.3)5/82/87/82/83/8•Infliximab21/20/22/20/20/2•Adalimumab21/21/21/20/21/2•Golimumab33/30/33/31/31/3•Certolizumab pegol10/11/11/11/11/1Anti-TNF with ustekinumab, n (%)2 (13.3)2/20/22/20/21/2•Adalimumab11/10/11/10/10/1•Golimumab11/10/11/10/11/1Ustekinumab and vedolizumab, n (%)5 (33.3)4/51/52/51/50/5CD, Crohn's disease; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; UC, ulcerative colitis. Open table in a new tab CD, Crohn's disease; IBD, inflammatory bowel disease; TNF, tumor necrosis factor; UC, ulcerative colitis. Our study is the largest case series to date examining the efficacy and safety of combining biologic agents with different mechanisms of action in the treatment of IBD. Before combining therapy, our cohort of patients had a significant medically refractory luminal disease course. Patient characteristics observed included a mean disease duration of 14.2 years, a mean of 3.8 failed biologics, with 66.7% of patients having had a previous surgical resection and 86.7% with a penetrating disease phenotype. This baseline presentation is significantly worse than the previously reported 16 patients in 5 case series and reports as well as the only randomized clinical trial, which assessed the safety and efficacy of combining infliximab with natalizumab or placebo. Despite the severity of disease in our cohort, 11 patients (73.3%) had symptomatic improvement as per the CD-PRO/SS and partial Mayo subscore. A total of 10 patients (66.7%) had reduction of their corticosteroid dose, and only 3 of 15 patients (20.0%) progressed to needing further surgery. Safety and adverse events were assessed and found a total of 3 hospitalizations (Salmonella gastroenteritis, Clostridioides difficile infection, and malnutrition). A total of 4 infections were noted that were treated with antibiotics. Only 1 person discontinued a biologic agent, vedolizumab, because of arthralgias after an infusion. Despite small numbers, these results suggest that combining biologics with different mechanisms of action may be safe and effective in the treatment of IBD. In particular, an anti-TNF agent or vedolizumab with ustekinumab may be the ideal combination, although much larger numbers and studies are needed.