A recent study (LE Targownik, EI Benchimol, J Witt et al. Inflamm Bowel Dis 2019; 25: 1718-28) shows that direct health care costs are increased with anti-TNF therapy.
In this retrospective study using the Manitoba IBD Database, the authors examined the direct costs associated with anti-TNF therapy initiation in 928 patients (676 CD, 252 UC). Only 84 subjects were <18 years.
- The median costs for health care in the year of anti-TNF initiation increased compared to prior year. In year prior to initiation, median costs were $4698 for CD and $6364 for UC; in the first year of anti-TNF treatment, costs rose to $39,749 and $49,327 respectively.
- Costs remained elevated through 5 years of anti-TNF therapy for continuous users with total median of $210,956 and $245,260 respectively
- There were reductions in non-drug costs. Inpatient and outpatient costs decreased in the year after anti-TNF initiation by 12% and 7% respectively, when excluding the costs of anti-TNFs. These observed savings are considerably less than the medication expenditures.
- Costs for medications are likely to improve with the introduction of biosimilars. Currently these are being used mainly in persons with a new diagnosis due to reticence to switch from originator product in established patients.
- The authors note that costs were overall higher with infliximab (IFX) than adalimumab (ADA) though “it is possible that patients with higher-severity disease are channeled toward IFX over ADA.”
- Indirect costs like ability to go to work and achieve educational potential could offset some of the direct costs. In a prior study in the U.S., ADA treatment was estimated to reduce indirect costs of “nearly $11,000 per person treated.”
- Some costs were not measured in the study including emergency room visits, over the counter medications and alternative health care use.
- This was not a randomized study; thus, it is impossible to know what costs of persons with similar disease who were untreated would have been.
My take: This study shows that saving money is not the main reason to use anti-TNF therapies; rather, their effects on improved health and fewer complications.
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Haystack Rock, Cannon Beach OR
D Piovani et al. Gastroenterol 2019; 157: 647-59. This study examined environmental risk factors for inflammatory bowel disease after extensive literature review and assessment of meta-analysis.
9 factors that were associated with increased risk of IBD:
- smoking (CD)
- urban living (CD & IBD)
- appendectomy (CD)
- tonsillectomy (CD)
- antibiotic exposure (IBD)
- oral contraceptive use (IBD)
- consumption of soft drinks (UC)
- vitamin D deficiency (IBD)
- Heliobacter species (non-Helicobacter pylori-like) (IBD)
7 factors that associated with reduced risk of IBD:
- physical activity (CD)
- breatfeeding (IBD)
- bed sharing (CD)
- tea consumption (UC)
- high folate levels (IBD)
- high vitamin D levels (CD)
- H pylori infection (CD, UC, and IBD)
EL Barnes et al. Inflamm Bowel Dis 2019; 1474-80. In this review which identified 12 studies and 4843 with an IPAA ( ileal pouch-anal anastomosis) for ulcerative colitis, 10.3% were ultimately diagnosed with Crohn’s disease. Link to full text and video explanation: The Incidence and Definition of Crohn’s Disease of the Pouch: A Systematic Review and Meta-analysis
EV Loftus et al. Inflamm Bowel Dis 2019; 1522-31. In this study with 2057 adalimumab-naive patients, “the proportion of patients in HBI remission increased from 29% (573 of 1969; baseline) to 68% (900 of 1331; year 1) and 75% (625 of 831; year 6). Patients stratified by baseline immunomodulator use had similar HBI remission rates.” Full text: Adalimumab Effectiveness Up to Six Years in Adalimumab-naïve Patients with Crohn’s Disease: Results of the PYRAMID Registry
The following study was summarized in previous blog: Oral Antibiotics For Refractory Inflammatory Bowel Disease Full text link: Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease
Washington Park, Portland, OR
Briefly noted: NE Burr et al. Clin Gastroenterol Hepatol 2019; 17: 2042-49.
In a retrospective cohort (1994-2013) using a primary care database from England, the authors identified decreasing risk of surgeries with Crohn’s diseae (CD).
- From 1994-2003, the risk of first surgery dropped from 44% to 21%.
- The risk of a second resection dropped as well, from 40% in 1994 to 17% in 2003 (with 10-year followup)
The reasons for this reduction are not certain but could include better clinical care or reduction in other risk factors (like smoking).
Atlanta Botanical Garden
A landmark study (BE Sands et al. NEJM 2019; 381: 1201-14) shows that ustekinumab (Stelara) can be an effective therapy for moderate-to-severe ulcerative colitis (UC); it is already an approved, established therapy for Crohn’s disease. This randomized placebo-controlled study included an 8-week induction trial (n=961) followed by a 44-week maintenance trial (n=523) for patients with response.
Clinical remission was defined as a total socre of ≤2 on the Mayo scale (range 0-12) and no subscore >11 on any of the four Mayo scale components.
- During induction, there was a similar clinical remission rate between those who received 130 mg fixed intravenous dose compared to those who received 6 mg/kg: 15.6% and 15.5% compared to 5.3% for placebo group.
- During maintenance, among patients receiving 90 mg every 8 weeks the clinical remission rate at 44 weeks was 43.8%, in those with 90 mg every 12 weeks the rate was 38.4%; placebo group was 24.0%.
- The response to ustekinumab occurred in those with or without previous treatment failure with biologic agents, though response was lower in both induction and maintenance in those with prior treatment failure. In both phases, at least 59% of participants had failed either or both anti-TNF agents or vedolizumab.
- In this study, there were similar serious adverse events with ustekinumab compared to placebo. In the treatment groups, there were two deaths (one from ARDS, one from esophageal varices) and 7 cases of cancer (3 nonmelanoma skin cancer, two colon cancer, one prostate, one renal). There was one death from testicular cancer in the placebo group. Also four patients in the ustekinumab group had opportunistic infections including CMV in two, legionella in one and HSV in one.
In terms of dosing, the authors note that there was greater improvement in calprotectin values during induction in the group who received 6 mg/kg compared to those who received 130 mg. At week 44, using more objective and stringent end points (eg. endoscopic improvement), greater clinical benefit was observed with the every 8 week regimen.
Visual abstract from NEJM Twitter Feed:
The following image depicts patients response during the maintenance phase –the lightest color is placebo, followed by every 8 weeks, and then the darkest color is every 12 weeks. The x-axis measures (left to right) are clinical remission, maintenance of clinical response at week 44, endoscopic improvement, corticosteroid-free remission, and remission at 44 weeks in those with remission after induction.
My take: Ustekinumab is more effective for placebo in patients with ulcerative colitis. More experience is needed to understand its long-term safety.
Related blog posts:
S Olivia et al (including Stanley Cohen from GI Care for Kids) Clin Gastroenterol Hepatol 2019; 17: 2060-7. “A Treat to Target Strategy Using Panenteric Capsule Endoscopy in Pediatric Patients with Crohn’s Disease” In this prospective study with 48 children with Crohn’s disease, pan-enteric capsule endoscopy (PCE) detected inflammation in 34 (71%) at baseline, 22 (46%) at week 24, and 18 (39%) at week 52. PCE results were used to manage treatment and resulted in change in therapy in 71% at baseline and 23% at week 24. Furthermore, PCE increased the proportions of patients in deep remission, up to 58% at week 52.
M Wright, et al. J Pediatr 2019; 210: 220-5. This case report of a 4 year-old boy with a perianal abscess and granulomatous colitis identified a NCF4 mutation causing severe neutrophil dysfunction. He developed osteomyelitis with anti-TNF therapy and did not respond to vedolizumab. He had an excellent outcome following a hematopoietic stem cell transplantation. This study reinforces the potential benefit of investigating VEO-IBD which could allow more targeted therapy. Related blog post: Patterns and Puzzles with Very Early Onset Inflammatory Bowel Disease
P Zapater et al. Inflamm Bowel Dis 2019; 25: 1357-66. This study with 112 patients with Crohn’s disease showed that serum interleukin-10 levels were directly related to infliximab and adalimumab levels. This suggests that serum anti-TNF levels are significantly influenced by immunological activation.
JE Axelrad et al. Clin Gastroenterol Hepatol 2019; 17: 1311-22. This study, using the Swedish National Patient Register, showed that gastrointestinal infection increased the odds of developing IBD in a nationwide case-control study. “Of the patients with IBD, 3105 (7%) had a record of previous gastroenteritis compared with 17,685 control subjects (4.1%). IBD cases had higher odds for an antecedent episode of gastrointestinal infection (aOR 1.64), bacterial gastrointestinal infection (aOR 2.02) and viral gastrointestinal infection (aOR 1.55)…a previous episode of gastroenteriitis remained associated with odds for IBD more than 10 years later (aOR 1.26).” The authors note that they cannot formally exclude misclassification bias, but it appears that enteric infections contribute to the development of IBD in susceptible individuals.
As noted in a previous blog (IBD Briefs August 2019), there have been numerous diets proposed to help with Crohn’s disease. The chart below illustrates the lack of any consensus.
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WE Bennett, MD Pfefferkorn.
Full Link: Editorial: “Mental Health Screening as the Standard of Care in Pediatric Inflammatory Bowel Disease” Thanks to Ben Gold for this reference.
Butwicka and colleagues1 have published a fascinating, landmark cohort study in this issue of JAMA Pediatricsassessing the prevalence of psychiatric diagnoses and symptoms among children with inflammatory bowel disease (IBD) in Sweden. The authors used a rigorous design that compared a cohort of more than 6000 pediatric patients with IBD with hundreds of thousands of healthy controls, as well as a separate cohort comprising the patients’ own siblings who did not have IBD. Butwicka et al1 computed hazard ratios for any psychiatric disorder, as well as for multiple specific disorders, and found a hazard ratio of 1.6 for any psychiatric diagnosis when comparing children with IBD with healthy controls. The statistical analysis is stellar and represents the best data we currently have on the intersection of pediatric IBD and mental health. Their study highlights a substantial risk in a vulnerable population and should trigger revision of guidelines and allocation of resources to support widespread screening and treatment for these dangerous conditions.
A Butwicka et al.
Full Text Link: Association of Childhood-Onset Inflammatory Bowel Disease With Risk of Psychiatric Disorders and Suicide Attempt
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Crater Lake, OR