Teaching Topic, Vedolizumab versus Adalimumab for Ulcerative Colitis, ORIGINAL ARTICLE Vedolizumab versus Adalimumab for Moderate-to-Severe Ulcerative Colitis B.E. Sands and Others    Sands et al. conducted the VARSITY trial, a phase 3b, randomized, double-blind, double-dummy, active-controlled superiority trial that compared the efficacy and safety of vedolizumab with those of adalimumab in patients with moderately to severely active ulcerative colitis. Clinical Pearls   What agents are typically used when conventional treatments for ulcerative colitis fail? Agents that are commonly used when conventional treatments (e.g., aminosalicylates, oral immunomodulators, and glucocorticoids) fail include tofacitinib, a small-molecule Janus kinase inhibitor, and biologic agents, such as tumor necrosis factor (TNF) inhibitors (e.g., infliximab, adalimumab, and golimumab) and vedolizumab, an anti-integrin antibody.   What types of patients were eligible for the trial by Sands et al.? Adults 18 to 85 years of age were eligible for inclusion in the trial if they had moderately to severely active ulcerative colitis, defined as a total score of 6 to 12 on the Mayo scale (total Mayo scores range from 0 to 12, with higher scores indicating more severe disease) and a subscore of at least 2 on the endoscopic component of the Mayo scale (subscores on each of the four components of the Mayo scale range from 0 to 3); colonic involvement of at least 15 cm; and had a confirmed diagnosis of ulcerative colitis at least 3 months before screening. Patients who had not previously used a TNF inhibitor and had no response or loss of response to conventional treatments were eligible. Patients who had discontinued treatment with a TNF inhibitor (except adalimumab) because of documented reasons other than safety were also eligible, with enrollment capped at 25%. All patients had not previously received vedolizumab. Morning Report Questions Q. How did vedolizumab compare to adalimumab for the treatment of moderate-to-severe ulcerative colitis in the VARSITY trial? A. In this comparative clinical trial of two biologic agents involving patients with moderately to severely active ulcerative colitis, clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission, were observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group. It is difficult to explain the inconsistency of the results between the secondary outcome of corticosteroid-free remission and the primary remission outcome. The trial did not require a specific schedule for glucocorticoid tapering, which can vary among practitioners. However, this limitation should not have resulted in differential effects in the two treatment groups. Q. What were some of the adverse event findings of the VARSITY trial? A. Adverse events occurred in 62.7% of the patients (240 of 383) in the vedolizumab group and in 69.2% (267 of 386) in the adalimumab group. Serious adverse events occurred in 11.0% of the patients (42 of 383) in the vedolizumab group and in 13.7% (53 of 386) in the adalimumab group. Exposure-adjusted incidence rates of infections and serious infections showed that both occurred less frequently with vedolizumab than with adalimumab (infections, 23.4 vs. 34.6 events per 100 patient-years; serious infections, 1.6 vs. 2.2 events per 100 patient-years). Herpes zoster infection was less frequent with vedolizumab than with adalimumab (0.5 vs. 4.2 per 100 patient-years), although Clostridium difficile infection was more frequent (1.1 vs. 0.6 per 100 patient-years). No patient received a diagnosis of progressive multifocal leukoencephalopathy.

Teaching Topic A Woman with Lung Cancer and Chest Pain CASE RECORDS OF THE MASSACHUSETTS GENERAL HOSPITAL Case 30-2019: A 65-Year-Old Woman with Lung Cancer and Chest Pain T.E. Guiney and Others    Myocarditis associated with the use of an immune checkpoint inhibitor can lead to arrhythmias, heart block, cardiogenic shock, or death. Clinical Pearls   What is the mechanism of action of nivolumab? Nivolumab, a monoclonal antibody directed against programmed death 1 (PD-1) receptor, is an immune checkpoint inhibitor; it functions by blocking immune-suppressing ligands PD-L1 and PD-L2 from interacting with PD-1 (or the PD-1 receptor) to restore T-cell function and an effective immune response. However, activation of the immune system may be associated with an immune-related adverse event such as myocarditis, although this event would be uncommon.   What were the findings of the CheckMate 057 trial? The phase 3 CheckMate 057 trial showed a significant survival benefit of nivolumab over docetaxel in patients with previously treated nonsquamous non-small-cell lung cancer (NSCLC). After more than 2 years of follow-up, nivolumab continued to provide an overall survival benefit with a manageable safety profile. On the basis of these data and the results from additional studies, inhibitors of PD-1 and PD-L1 have become standard second-line treatment options for patients with advanced NSCLC who were previously treated with chemotherapy. The PD-1 inhibitor pembrolizumab has received regulatory approval as a first-line treatment — both as monotherapy and in combination with chemotherapy. Owing to the activity of immune checkpoint inhibitors as both first-line and second-line therapy, it is reasonable to postulate that most patients with NSCLC will receive an immune checkpoint inhibitor during their disease course. Morning Report Questions Q. What is the prognosis of immune checkpoint inhibitor–associated myocarditis? A. The first case of myocarditis related to the use of an immune checkpoint inhibitor was reported in 2014. Since then, numerous case reports, original research articles, and summary statements detailing the characteristics, pathological features, outcomes, and knowledge gaps regarding immune checkpoint inhibitor–associated myocarditis have been published. Data are evolving, but our understanding of this condition remains poor. The incidence ranges from 0.06% to 1.1%. Although the incidence is debated, consistent data have shown that outcomes are poor, with death from cardiovascular causes reported to occur in 20 to 40% of cases. In addition, unlike other forms of myocarditis, immune checkpoint inhibitor–associated myocarditis may lead to major adverse cardiac events despite a preserved ejection fraction. Q. How is immune checkpoint inhibitor–associated myocarditis managed? A. Management of this condition typically includes immunosuppression with glucocorticoids. Early data from an international, multicenter registry have suggested that the use of high-dose glucocorticoids may be associated with a decreased incidence of subsequent major adverse cardiac events; however, the incidence of major adverse cardiac events remains high even with use of very high doses of glucocorticoids. Alternative immunosuppressive approaches for the management of immune checkpoint inhibitor–associated myocarditis have included the use of mycophenolate, monoclonal antibodies to CD52, plasma exchange, cytotoxic T-lymphocyte–associated antigen 4 agonists, antithymocyte globulin, and infliximab. However, the support for these approaches is limited to single case reports, which are often associated with publication bias.

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QUOTE OF THE WEEK “In conclusion, our prospective, randomized BARD trials comparing several strategies of treatment escalation for asthma in children and in adolescents and adults who had at least one grandparent who identified as black showed that outcomes differed in children and adults, and the results in these children differed from those previously reported in studies involving white children. In contrast to black adults and white persons of all ages, almost half the children who had one grandparent who identified as black and who had poorly controlled asthma had a superior response to an increased dose of an inhaled glucocorticoid over the addition of a LABA [long-acting beta-agonist].” M.E. Wechsler and Others, Original Article, “Step-Up Therapy in Black Children and Adults with Poorly Controlled Asthma”