Incidence of fibrosing colonopathy with pancreatic enzyme replacement therapy in patients with cystic fibrosis.

BACKGROUND: High daily doses of pancreatic enzyme replacement therapy (PERT) were historically associated with risk of fibrosing colonopathy (FC) in people with cystic fibrosis (pwCF), leading to development of PERT dosing guidelines and reformulated products. This study quantified incidence of FC in pwCF treated with PERT following those measures. METHODS: This large prospective cohort study included eligible pwCF enrolled in the Cystic Fibrosis Foundation Patient Registry with ≥1 clinic visit in 2012-2014 and follow-up through 2020. Data on PERT exposure, demographics, and medical history were collected. Clinical data, imaging, and histopathology of suspected cases were examined by an independent adjudication panel of physicians familiar with this complication. RESULTS: Base Study Population included 26,025 pwCF who contributed 155,814 person-years [mean (SD) 6.0 (2.0) years] of follow-up. Over 7.8 years, 29 pwCF had suspected FC; three cases were confirmed by adjudication, 22 cases were confirmed as not FC, and four cases were indeterminate. There were 22,161 pwCF exposed to any PERT, with mean PERT use time of 5.583 person-years and mean daily dose of 8328 U lipase per kg per day. All three confirmed cases and four indeterminate cases of FC occurred during current use of PERT. Incidence rates per 1000 person-years exposed were 0.0242 (95 % CI [0.0050, 0.0709]) for confirmed FC and 0.0566 (95 % CI [0.0227, 0.1166]) for indeterminate or confirmed FC. CONCLUSIONS: The incidence of FC in pwCF is very low in the era of current treatment guidelines and more stringent quality standards for PERT products.

Infliximab efficacy in rheumatoid arthritis after an inadequate response to etanercept or adalimumab: results of a target-driven active switch study.

OBJECTIVE: Evaluate efficacy of infliximab with response-driven dosing in patients with active RA. RESEARCH DESIGN AND METHODS: Patients (n = 203) with active RA despite methotrexate + etanercept/adalimumab, participated in this active-infliximab-switch study. Infliximab 3 mg/kg was infused at Weeks 0, 2, 6, 14, and 22 with escalation to 5 or 7 mg/kg depending on EULAR response at Weeks 14 and 22. The primary endpoint was EULAR response at Week 10. Safety was assessed through Week 30. Infliximab levels and antibodies to infliximab (ATI) were measured at Weeks 0, 6, 14, and 26. CLINICAL TRIAL REGISTRATION: NCT 00714493, EudraCT 2007-003288-36. RESULTS: Of 197 evaluable patients, 120/77 previously received etanercept/adalimumab. Baseline mean (SD) swollen and tender joint counts were 17.3 (10.54) and 30.2 (16.89), respectively; mean DAS28-ESR was 6.19 (0.981). At Week 10, 98 (49.7%; 95% CI: 42.6%, 56.9%) patients achieved EULAR response, with a significantly improved DAS28-ESR score (mean [SD] change -1.1 [1.15]; p < 0.001). EULAR response was achieved by 41.7%/62.3% of patients previously receiving etanercept/adalimumab (p = 0.006). At Week 26, 51.8% (95% CI: 44.6%, 58.9%) of patients achieved or maintained EULAR response. Infliximab dose was escalated in 100 patients, 52% of whom achieved EULAR response at Week 26. Median serum concentration levels at Week 26 showed that dose escalation helped EULAR non-responders achieve levels similar to or higher than the levels seen in responders. ATI were associated with lower serum concentrations of infliximab, consistent with lower efficacy rates among ATI-positive patients. CONCLUSION: Infliximab, in treat-to-target settings with individual dose escalation, demonstrated significant efficacy at Weeks 10 and 26 in patients switched to infliximab after inadequate response to etanercept/adalimumab. The observed efficacy indicated that the switch to infliximab and ability to increase dose in a targeted fashion were beneficial. KEY LIMITATIONS: Given the relatively short duration of study follow-up, these safety findings require confirmation in a longer-term study.

A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically naive and switched rheumatoid arthritis patients: results from the US CORRONA registry.

PURPOSE: To compare the effectiveness of anti-tumour necrosis factor (TNF) agents in biologically naive and 'switched' rheumatoid arthritis (RA) patients. METHODS: RA patients enrolled in the CORRONA registry newly prescribed adalimumab (n=874), etanercept (n=640), or infliximab (n=728) were stratified based on previous anti-TNF use. Clinical effectiveness at 6, 12 and 24 months was examined using the modified American College of Rheumatology response criteria (mACR20/50/70) and achievement of remission (28-joint disease activity score (DAS28) and clinical disease activity index (CDAI)) in unadjusted and adjusted analyses. The persistence of anti-TNF treatment was examined using Cox proportional hazard models. RESULTS: Among 2242 patients (1475 biologically naive, 767 switchers), mACR20, 50 and 70 responses were similar (p>0.05) for adalimumab, etanercept and infliximab at all time points, as were rates of CDAI and DAS28 remission (p>0.05). Response and remission outcomes were consistently inferior for switched versus biologically naive patients. The adjusted OR for achieving an mACR20 response was 0.54 (95% CI 0.38 to 0.76) in first-time switchers and 0.42 (95% CI 0.23 to 0.78) in second-time switchers versus biologically naive patients at 6 months. The adjusted OR for achieving DAS28 remission were 0.29 (95% CI 0.15 to 0.58) for first-time switchers and 0.26 (95% CI 0.08 to 0.84) for second-time switchers. Persistence was higher in biologically naive patients, for whom persistence was highest with infliximab. CONCLUSIONS: No differences in rates of drug response or remission were observed among the three anti-TNF. Infliximab was associated with greater persistence in biologically naive patients. Response, remission and persistence outcomes were diminished for patients who switched anti-TNF.

Effects of Aluminum/Magnesium Hydroxide and Calcium Carbonate on Esophageal and Gastric pH in Subjects with Heartburn.

This single-blind crossover trial compared the effects of single oral doses of two antacids on esophageal and gastric pH in subjects with heartburn. Gastric and esophageal pH were assessed in 83 subjects from 1 h before to 4 h after a refluxogenic meal. Subjects received two chewable tablets of a high-potency aluminum/magnesium hydroxide [Al(OH)3/Mg(OH)2] formulation (Mylanta Double-Strength(TM)) or a calcium carbonate [CaCO3] formulation (Tums E-X(TM)), or placebo 1 h after the meal. Both antacid formulations significantly increased esophageal pH, as compared with placebo. Onset of action was faster with the Al(OH)3/Mg(OH)2 formulation than with the CaCO3 in 41 subjects, slower in 13 subjects, and identical in 29 subjects. Area under the esophageal pH--time curves after dosing were significantly greater for Al(OH)3/Mg(OH)2 than for CaCO3 (p < 0.05) and significantly greater for CaCO3 than for placebo (p < 0.05). The duration of Al(OH)3/Mg(OH)2 action in the esophagus was 82 min and 60 min for CaCO3 (p < 0.05). In the stomach, only Al(OH)3/Mg(OH)2 increased gastric pH compared with placebo. After ingestion of calcium carbonate, gastric pH usually remained at or below placebo values, a finding consistent with a calcium carbonate-induced "acid rebound." The duration of Al(OH)3/Mg(OH)2 action in the stomach was 26 min. These findings demonstrate the efficacy and relative superiority of this particular aluminum/magnesium hydroxide formulation compared with the calcium carbonate preparation at increasing esophageal and gastric pH. However, the magnitude and duration of action of both antacids on esophageal pH, in contrast to minimal effects on gastric pH, suggest strongly that the lower esophagus is the primary site of antacid activity in relief of heartburn.

Comparative Effects of Liquid Antacids on Esophageal and Gastric pH in Patients with Heartburn.

This double-blind crossover trial compared the postmeal effects of single doses of liquid antacids on esophageal and gastric pH in patients with a history of heartburn. Treatment consisted of one of two antacids containing the same active components---aluminum and magnesium hydroxide---but different in vitro acid-neutralizing capacities (ANCs). The pH was assessed continually from 1 h before a refluxogenic meal to 4 h after its completion in 24 subjects who received 20 ml of Mylanta((R)) Double Strength (MYL-20: ANC = 101.6 mEq), 20 or 30 ml of Extra-Strength Maalox((R)) Plus (MA-20, MA-30: ANC = 116.2 and 174.3 mEq, respectively), or placebo (ANC = 0) in random order. Esophageal pH increased rapidly and significantly (p < 0.05) to peak values of 7.0--7.4 with antacid. The increase in mean esophageal pH values was significantly higher (p < 0.05) than placebo for 30 min with MA-20 and for at least 70 min with MYL-20 and MA-30. In contrast, gastric pH rose slowly to mean peaks of 2.9--3.1 with antacid. During this interval, only MYL-20 was associated with significant improvements (p < 0.05 versus placebo) in total number of reflux episodes and total time that esophageal pH measured >4. Thus, ANC alone is not a useful guide in predicting in vivo antacid behavior, as in this study where the antacid dose with the lowest ANC demonstrated a duration of action as long or longer than that of antacid doses with higher ANC values. The rapid, prolonged increases in esophageal pH that preceded modest changes in gastric pH strongly suggest that the lower esophagus is the primary site of antacid action for heartburn relief.

Efficacy and Tolerability of Famotidine in Preventing Heartburn and Related Symptoms of Upper Gastrointestinal Discomfort.

This randomized, double-blind, placebo-controlled, four-way crossover trial was designed to compare the efficacy of famotidine and placebo in preventing meal-provoked upper gastrointestinal symptoms. One hundred twenty-one subjects (58 men and 63 women), aged 20--61 years, were randomly assigned to one of four treatment sequences which included single oral doses of placebo, famotidine 5 mg, famotidine 10 mg, and famotidine 20 mg, spaced approximately 7 days apart. To be eligible for randomization, subjects had to have at least a 2-month history of heartburn and acid/sour stomach occurring at least three times per week. Treatment was administered 1 h prior to ingestion of test meals (chili and wine). Rescue antacid medication (Maalox((R))) was available for subjects who required additional relief. Heartburn severity. acid/sour stomach, and overall discomfort were evaluated on a six-point scale immediately prior to each test meal and every 15 min thereafter for 5 h. A global evaluation of the test medication, using a five-point scale, was performed prior to rescue medication use or at the end of each treatment session. Heartburn and peak acid/sour stomach were rated as significantly milder following prophylactic treatment with famotidine 5, 10, and 20 mg compared to placebo. Treatment with all three doses of famotidine was rated as "good" or "excellent" by significantly more subjects (58--63%) than following treatment with placebo (38%). In addition, rescue medication was used by significantly fewer subjects following famotidine (17--18%) compared to placebo (37%). Famotidine was generally well tolerated in this trial, with type and frequency of reported adverse experiences similar to that observed following placebo. These results indicated that famotidine doses of 5, 10, and 20 mg were significantly more effective than placebo in preventing symptoms of upper gastrointestinal distress when administered 1 h in advance of meal provocation.