ATS 2017: News in Respirology - Asthma

ATS 2017. A4678 - Benralizumab Significantly Reduced Oral Corticosteroid Dosages and Asthma Exacerbation Rates for Patients with Severe, Uncontrolled Asthma: Results of the ZONDA Phase III Trial

P. Nair, MD, PhD, FRCP, FRCPC (Hamilton, ON, Canada) S. E. Wenzel, MD (Pittsburgh, PA, United States of America) K. Rabe, MD, PhD, FERS (Großhansdorf, Germany) A. Bourdin, MD (Montpellier, France) N. Lugogo, MD (Durham, NC, United States of America) P. Kuna, MD, PhD (Łódź, Poland) P. Barker, PhD (Gaithersburg, MD, United States of America) S. Sproule, PhD (Gaithersburg, MD, United States of America) S. Ponnarambil, MD (Cambridge, United Kingdom) M. Goldman, MD, PhD (Gaithersburg, MD, United States of America)

Results: Of 220 patients who were randomized and received treatment, 207 (94.1%) completed treatment. Benralizumab significantly reduced final OCS dosages by a median of 75% with the Q4W and Q8W regimens (p<0.001) compared with placebo (25%; table). The odds of a reduction in OCS dosage were 4.09-times greater (Q4W; p<0.001) and 4.12-times greater (Q8W; p<0.001) than with placebo. Benralizumab also significantly reduced annual asthma exacerbation rates by 55% (Q4W; p=0.003) and 70% (Q8W; p<0.001) vs. placebo, despite reduction in OCS dosages in the active treatment groups (table). Adverse events were numerically lower for the benralizumab Q4W and Q8W groups vs. placebo (68.1% and 75.3% vs. 82.7%, respectively). 

Conclusion: Benralizumab was well-tolerated and demonstrated significant, clinically relevant OCS-sparing benefits and asthma exacerbation rate reduction compared with placebo.


CARE FACULTY PERSPECTIVE

In this largest study to date of prednisone-dependent patients, benralizumab administered in dose of 30 mg SC every 8 weeks allowed the dose of prednisone to be reduced by up to 75% while still reducing exacerbations by 70% and preserving FEV1.  The odds of reducing prednisone was more than four-fold compared to placebo.  The magnitude of treatment effect was more than previously reported with mepolizumab.  It remains to be seen if the unique mechanism of action of antibody-dependent cytotoxic killing of eosinophils that express the IL-5 receptor leads to any long-term harmful consequences.

Provided by: Dr. Parameswaran Nair
CARE Respirology Faculty
Professor of Medicine, McMaster University
Staff Respirologist, St. Joseph’s Healthcare Hamilton

ATS 2017: News in Respirology - Cystic Fibrosis

ATS 2017. A4729 - Ivacaftor/Lumacaftor Improves Six Minute Walk Test Distance and Improves Lung Clearance Index and Functional Residual Capacity in Cystic Fibrosis Patients Homozygous for DF508 with Very Severe Lung Disease

P. A. Wark, MD, PhD (New Lambton, NSW, Australia), K. Cookson, B Nur (New Lambton, NSW, Australia), T. Thiruchelvenem, B Pharm (New Lambton, NSW, Australia), D. Dorahy, PhD (New Lambton, NSW, Australia), J. Brannan, PhD (New Lambton, NSW, Australia)

Conclusion: In subjects with severe lung disease treatment with Lumacaftor/Ivacaftor led to a significant improvement in 6MWT evident by 4 weeks, that continued to improve at 12 weeks. There was no improvement seen in FEV1, though the MBW demonstrates a change in LCI and a significant decline in FRC after 12 weeks of treatment.


CARE FACULTY PERSPECTIVE
 

Study by Wark et al indicates that combination Ivacaftor/Lumacaftor therapy improves functional residual capacity and six-minute walk test distance in patients homozygous for DF508 with severe lung disease (FEV1>40% predicted). Ivacaftor/Lumacaftor (Orkambi) therapy may lead to functional improvement by reducing airway mucus plugging and air trapping.  

Treatment paradigms for patients with CF have shifted with CFTR targeting therapies.  Some CFTR targeting therapies are already approved for clinical use (such as Orkambi) and others are in clinical or pre-clinical testing.  Unresolved issues for the treating physician include which criteria to use to select patients for these treatments and how to assess treatment success.  This will lead to more options and sequencing considerations.  However, fundamental/unresolved issues require attention from treating physicians, so that they may can have clarity when treating CF patients.  In order to frame this practically, a case follows.      

Provided by Dr. Hartmutt Grasemann
CARE Respirology Faculty
The Hospital for Sick Children
Professor, University of Toronto

 

DDW 2017: News in Gastroenterology - Ulcerative Colitis

DDW 2017. Mo1652. IMPACT OF PROINFLAMMATORY CYTOKINES AND MESALAMINE ON THE EXPRESSION OF THE TIGHT JUNCTION PROTEIN CLAUDIN-1 IN INTESTINAL EPITHELIAL CELLS

 

Results: IFN and IL-13 had no effect on claudin-1 expression whereas stimulation of intestinal epithelial cells with IL-1, IL-6, TNF and a combination of IFN with TNF induced a dose- and time-dependent increase in claudin-1 expression. Concurrent treatment with mesalamine applied from the apical side of the monolayer partially prevented increased claudin-1 expression induced by proinflammatory cytokines. Data on the subcellular localization of claudin-1 and activation of key signaling pathways are currently under investigation and will be presented at the meeting.

Conclusions: Our results identify proinflammatory cytokines controlling claudin-1 expression in intestinal epithelial cells. The ability of mesalamine to counteract claudin-1 upregulation by these cytokines might provide a molecular basis for its suggested role as a chemo preventive agent in IBD-associated colorectal cancer.

CARE Faculty Perspective: This interesting study provides more fodder for the longstanding debate about the direct chemopreventive effects of 5-ASA. 

DDW 2017: News in Gastroenterology - Crohn's Disease

DDW 2017. 718. SUPERIOR ENDOSCOPIC AND DEEP REMISSION OUTCOMES IN ADULTS WITH MODERATE TO SEVERE CROHN'S DISEASE MANAGED WITH TREAT TO TARGET APPROACH VERSUS CLINICAL SYMPTOMS: DATA FROM CALM

 

Results:
Figure. Primary endpoint at 48 Weeks after Randomization

Conclusions: This is the first study showing that the treat to target approach leads to superior endoscopic and deep remission outcomes in CD compared with symptom-driven care.

CARE Faculty Perspective: This novel ‘treat to target’ concept involves monitoring patients with CD using biomarkers of inflammation, CRP, and FC, to assist in timely treatment. While this is a preliminary study, we may want to consider changing our treatment approach moving forward, as this study has demonstrated that T2T method leads to better outcomes than conventional symptom-driven care.

DDW 2017: News in Gastroenterology - Functional Gastrointestinal Disorders

DDW 2017. 263. INTESTINAL, NON-INTESTINAL, AND EXTRA-DIGESTIVE RESPONSE TO LINACLOTIDE IN PATIENTS WITH IRRITABLE BOWEL SYNDROME WITH CONSTIPATION: RESULTS AT WEEK 4 PREDICT SUSTAINED RESPONSE

 

Results: 96 patients were eligible and treated (ITT analysis) after a 4-week screening period; 60 patients were included in the per protocol (PP) analysis. The majority were female (91; 95%) and mean age was 47 years. Mean baseline IBSSS score was 371 and mean time from diagnosis was 7.5 years (ITT). At Weeks 4 and 12, 23% and 25% of patients (ITT), and 32% and 37% of patients (PP), respectively, had a clinical response based on subjective improvement and IBSSS score. At Weeks 4 and 12, 64% and 55% of patients had subjective responses, and 24% and 32% had IBSSS score responses, respectively (ITT). If one of both criteria were considered, 61.5% (ITT) and 80% (PP) of patients obtained some benefit at Week 12. Baseline variables were not associated with response at Week 12, but response at Week 4 was independently associated with Week 12 response (OR: 6.5 [95% CI: 2.1, 19.8]). Digestive non-intestinal and extra-digestive symptom scores were significantly improved by Weeks 4 and 12 (Table). The most common adverse event was diarrhea (n=39; 21%). No serious adverse events occurred.

Table. Digestive non-intestinal and extra-digestive symptom scores (ITT population) 

 

Includes reflux and dyspepsia; bIncludes back pain, headaches, chest pain, dizziness, fainting spells, feeling heart pound or race, shortness of breath, pain or problems during sexual intercourse, pain in arms, legs, or joints, feeling tired or having low energy, menstrual cramps or other problems with periods (women only), and trouble sleeping *p=0.001 vs. baseline; **p<0.001 vs. baseline SD, standard deviation

Conclusions: Linaclotide relieves intestinal, non-intestinal, and extra-digestive symptoms in patients with clinically relevant IBS-C. Baseline characteristics were not predictive of response at Week 12, but response at Week 4 was independently associated with a sustained response at Week 12.

CARE Faculty Perspective: Linaclotide is an oral guanylate cyclase-C receptor antagonist approved in Canada for the treatment of moderate to severe IBS-C in adults. Previous trials have confirmed that linaclotide is a safe and effective agent that is able to reduce abdominal pain – one of the most highly reported reasons of why patients seek treatment.

Digestive non-intestinal and extra-digestive symptom scores were significantly improved already by week 4. From this study we can infer that if a patient responds to treatment at week 4, they are likely to have a sustained response at week 12.

DDW 2017: News in Gastroenterology - Functional Gastrointestinal Disorders

DDW 2017. Tu1612. IRRITABLE BOWEL SYNDROME PATIENT EXPERIENCE IN CANADA

 

Results: Respondents from every province and territory totalled 2,961. 90% were between 30-69 years of age, 86% female, 97% were adults with IBS. 53% had IBS for more than 10 years. 35% had IBS-D, 18% IBS-C, 41% IBS-M, and 6% unsure. In IBS-C patients, abdominal pain was identified as a distinct predominant symptom. Those with IBS-D experienced many symptoms, with abdominal pain, bloating, urgency, and diarrhea identified as highly concerning. 31% experienced severe abdominal pain in the last 3 months, with severe pain being constant in a high proportion. 62% of patients indicated they experienced pain continuing after bowel movement. The top factors driving patients to see their physician were pain/discomfort and impact of IBS on their personal/professional/daily life. Approximately 93% and 49% of patients consulted with a family doctor and gastroenterologist, respectively, for their IBS. 60% had a colonoscopy. 12% have been hospitalized for IBS. 76% indicated that their symptoms interfere with everyday life and 46% missed work or school due to IBS. Most IBS patients use ≥2 medications on a regular basis to control their symptoms yet only 21% are confident their symptoms are under control. Compounding the issue, 16% are unable to afford any of their prescribed medications, and 26% can only afford some of them.

Conclusions: Canadian IBS patients suffer from multiple symptoms, with the pain experienced by patients being the prime motivating factor to seek care. 79% have symptoms not under control. The conventional standard of care for IBS requires many different treatments to manage the multiple symptoms, with the majority of IBS patients requiring 2 or more treatments on a regular basis. IBS patients experience a wide range of symptoms and comorbidities. It can be a struggle for them to find treatments that are effective and affordable.

CARE Faculty Perspective: The most common complaints from patients include abdominal pain and constipation and/or diarrhea. Real-world data is limited, so this study aimed to look how IBS affects people in Canada. A questionnaire was distributed via the Gastrointestinal Society in Canada and included questions about symptom severity, medication use, experience with health care system, quality of life, etc.

The key finding from this survey is that 79% of patients do not have their IBS symptoms under control. This is a huge amount of people whose quality of life may be severely affected. More awareness on how to treat symptoms with appropriate treatment may be needed across Canada to ensure this rate is reduced.

DDW 2017: News in Gastroenterology - Upper Gastrointestinal Disorders

DDW 2017. 971: AGE OF HELICOBACTER PYLORI ERADICATION AND SUBSEQUENT RISK OF GASTRIC CANCER DEVELOPMENT: A POPULATION-BASED STUDY

Results: Among the 63,605 eligible HP-infected subjects (median age 54.8 years, 46.6% male) who had received a course of clarithromycin-based triple therapy, 169 (0.27%) developed GC with a median follow-up of 7.6 years (Incidence: 3.48 per 10,000 person-years). The incidence of gastric cancer in the youngest age group (<40 years) was very low (0.42 per 10,000 person-years) whereas the corresponding incidence rates in the 40-60 and >60-year age groups were 2.12 and 7.12 per 10,000 person-years, with a significant difference among the three groups (log rank p<0.001; Figure). When compared with the group who received HP therapy <40 years, there was a progressive increase in the risk of cancer in the older age groups (age group 40-60: HR 5.6, 95% CI 1.7-17.8; age group ≥60: HR 17.1, 95% CI 5.4-54.8).

Conclusions: In this large population-based study, we showed that the risk of gastric cancer development was very low in individuals who had received HP therapy before the age of 40. For prevention of gastric cancer, HP eradication shall be given before the age of 40.

CARE Faculty Perspective: The goal of this study was to determine the risk of developing gastric cancer after receiving HP eradication therapy among different age groups in a large cohort of HP infected subjects. It appears that patients over 60 have the highest rate of developing gastric cancer. In order to prevent this, HP eradication treatment should be given before the age of 40.