In patients with Crohn’s disease, dose escalation of biologic therapy (eg. anti-TNF agents, vedolizumab) has been shown to be helpful in recapturing response to treatment. In a retrospective study with 110 patients, Ollech et al explore the outcomes in those who had their subcutaneous ustekinumab interval shortened to 4 weeks (from every 8 weeks).
Following dose interval shortening, the patients’ median Harvey Bradshaw Index (HBI) decreased from 4.5 to 3 ( P = .002), the median level of CRP decreased from 8 mg/L to 3 mg/L ( P = .031), and median level of fecal calprotectin decreased from 378 μg/g to 157 μg/g ( P = .57).
Among patients with active disease (HBI >4, CRP ≥/=5mg/dL, fecal calprotectin >250ug/g, or endoscopic evidence for disease activity), dose interval shortening was associated with a 28% clinical remission (an HBI score ≤4), and 50% had reduced levels of fecal calprotectin; 36% achieved endoscopic remission.
The authors did not identify serious adverse events with dose shortening.
My take: Prospective studies are needed. This study indicates that more frequent dosing improves outcomes in a significant fraction of those with active disease.
Unrelated article: C-H Lo et al. Clin Gastroenterol Hepatol 2021; 19: 87-95. Healthy Lifestyle Is Associated With Reduced Mortality in Patients With Inflammatory Bowel Diseases In this study, using data from three large cohort studies, the authors assessed the impact of 5 healthy lifestyle factors: never smoking, body mass index 18.5–24.9 kg/m 2, vigorous physical activity in the highest 50% with non-zero value, alternate Mediterranean diet score ≥4, and light drinking [0.1–5.0 g/d]. Key finding:
Compared to patients with IBD with no healthy lifestyle factors, patients with IBD with 3–5 healthy lifestyle factors had a significant reduction in all-cause mortality (hazard ratio [HR], 0.29; 95% CI, 0.16–0.52; Ptrend < .0001).
My take: Like the general population, healthy lifestyle choices are important in individuals with IBD; this study provides some data on the effects on outcomes.
“The U.S. Food and Drug Administration (FDA) is alerting the public that preliminary results from a safety clinical trial show an increased risk of serious heart-related problems and cancer with the arthritis and ulcerative colitis medicine Xeljanz, Xeljanz XR (tofacitinib) compared to another type of medicine called tumor necrosis factor (TNF) inhibitors. FDA required the safety trial, which also investigated other potential risks including blood clots in the lungs and death. Those final results are not yet available….
Patients should not stop taking tofacitinib without first consulting with your health care professionals, as doing so may worsen your condition. Talk to your health care professionals if you have any questions or concerns.”
In this retrospective observational longitudinal cohort study with 3007 patients with IBD from the ImproveCareNow Network, the authors found a high rate of continued linear growth after expected growth plate closure (15 years in females, 17 years in males).
80% manifested continued growth beyond the time of expected growth plate closure, more commonly in CD (81%) than UC (75%; P = 0.0002)
Median height gain was greater in males with CD (1.6 cm) than in males with UC (1.3 cm; P = 0.0004), and in females with CD (1.8 cm) than in females with UC (1.5 cm; P = 0.025)
My take: This study provides additional information about delayed skeletal maturation in the pediatric population with inflammatory bowel disease. Interestingly, the rate of continued growth with ulcerative colitis was nearly as high as with Crohn’s disease.
In the article, they note “the exception is for any live-attenuated virus vaccines or replication-competent viral vector vaccines that come to market.” Currently, all of the vaccines are inactivated (not live-attenuated).
These recommendations apply to approved populations which currently do not include pediatric patients or patients who are pregnant.
A recent review (JT Chang. NEJM 2020; 383: 2652-2664. Pathophysiology of Inflammatory Bowel Diseases) provides an in-depth description of the pathophysiology of inflammatory bowel disease (IBD). Digesting the article is akin to putting together a 1000 piece puzzle due to the complex interactions.
Some of the Key Points:
Based on genomewide association studies, there are “more than 240 risk variants that affect intracellular pathways recognizing microbial products (eg. NOD2); the autophagy pathway, which facilitates recycling intracellular organelles and removal of intracellular microorganisms (eg. ATG16L1); genes regulating epithelial barrier function (eg. ECM1); and pathways regulating innate and adaptive immunity (eg. IL23R and IL10).”
In this article, Figure 1 and 2 describe the intestinal mucosal immune system in health and disease. At baseline, this system promotes an antiinflammatory state “by virtue of active down-regulation of immune responses. For example, unlike macrophages in other parts of the body, intestinal macrophages do not produce inflammatory cytokines” after exposure to bacteria.
Dysbiosis is present with IBD; however, studies have been “unable to infer causal relationships.”
Germ-free mice, when given fecal material from patients with IBD have increased susceptibility to colitis as compared to those who received fecal material from a healthy person.
Thus, this leads to potential for mitigating intestinal inflammation by modulation of the microbiome.
However, the authors note that humans are colonized by trillions of viral, fungal, bacterial, and eukaryotic microbes.
Other components of IBD pathophysiology: reduced mucus layer, increased microbial adherence, dysregulation of tight junctions/increased permeability, dysfunctional Paneth cells, TNF, IL23, IL12, IL6, IL 17A, IL17F, IL22, Interferon-gamma, integrins, JAK inhibitors, T-cells
My take: This article is a useful reference detailing the complexity of IBD pathophysiology and tries to summarize a whole textbook of information into 12 pages.
This study looked at 105 patients receiving combination therapy; the a median duration of combination therapy was 2.1 years, with infliximab and either methotrexate (53) or azathioprine (52). 89 patients had Crohn’s disease.
11 (10.5%) patients experienced a clinical relapse over a median duration of follow-up of 12.0 months after stopping the immunomodulator.
In the patients who did not relapse, the median IFX trough level at IM discontinuation was 6.2; the IFX trough level was 3.8 μg/mL in those who relapsed.
In their discussion, the authors urge caution in discontinuation of immunomodulators in those with clinically-severe Crohn’s disease and those with low infliximab levels.
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“Randomized controlled trials published more than a decade ago demonstrated that exclusive enteral nutrition, wherein all table foods are eliminated from a diet and the patient relies on an elemental diet alone for nutrition, was effective in not just inducing clinical remission but also improving inflammatory biomarkers.”
“More recent rigorous studies have demonstrated that the effects of exclusive enteral nutrition can be mimicked either by a selected, less-restrictive diet (such as CD-TREAT4), which is more sustainable, or by combining partial enteral nutrition with an elimination diet that is quite diverse (such as CDED5).”
“Exclusive enteral nutrition (EEN) has been studied the most rigorously of all diets in IBD and has demonstrated the greatest benefit, compared with other diet studies in IBD. EEN requires the intake of elemental, semi-elemental, or polymeric formulas to meet all nutritional requirements without additional intake of food for 6-8 weeks. Studies have been performed mostly in pediatric populations and have shown effectiveness in induction of remission with reduction in inflammatory markers, including C-reactive protein, erythrocyte sedimentation rate, and fecal calprotectin, and even mucosal healing. EEN has not worked out as well for adult populations, because of the poor tolerability of exclusive intake of enteral formulas.”
“Beyond EEN, there are many diets that have been considered … only the SCD and Crohn’s disease exclusion diets have shown improvement in clinical remission and reduction in inflammatory markers.”
“Most dietary studies are underpowered, lack a control arm, and do not include endoscopic endpoints. The current body of evidence remains insufficient to support the use of diet alone for the treatment of IBD.”
My take: Except for exclusive enteral nutrition (EEN) which is quite challenging, dietary therapies have not been proven as effective long-term stand-alone treatments. In patients who choose dietary therapy, careful monitoring is particularly important.
In this systematic review, a total of 995 adult patients were included from 18 observational studies (4 prospective and 14 retrospective), 1 nonrandomized controlled trial, and 1 subgroup analysis of a randomized controlled trial.
Biologic dose de-escalation was associated with relapse rates as high as 50% at 1 year. Overall, clinical relapse occurred in 0%–54% of patients who dose de-escalated biologic therapy (17 studies).
Lower rates of relapse (10%–25%) were reported in studies involving patients with endoscopic and/or histologic remission
These results are in agreement with a previous meta-analysis, which found a 1-year risk of relapse after discontinuation of anti-TNF therapy of 36% in CD and 28% in UC ( Gisbert JP, et al.. Am J Gastroenterol 2016;111:632–47).
My take: This study shows that dose de-escalation of biologic therapy in IBD seems to be associated with high rates of clinical relapse
In this national multicenter retrospective cohort study in 207 adult patients with either active or inactive perianal Crohn’s disease (pCD) who received ustekinumab (2017-2018). The majority had received multiple biologics (~85% had at least 2 anti-TNF agents, 28% had received vedolizumab) and prior anal surgeries (mean 2.8).
Methods: Success of ustekinumab was defined by (i) clinical success at 6 months of treatment assessed by the physicians’ judgment, with (ii) no need for dedicated medical treatment for perianal lesions (antibiotics and/or topics) nor (iii) unscheduled surgical treatment. For perianal disease evaluation, clinical success was defined in the study protocol, by the absence of draining pus for fistulas, and no anal ulcers
In patients with active pCD, success was reached in 57/148 (38.5%) patients.
Among patients with setons at initiation, 29/88 (33%) had a successful removal.
In patients with inactive pCD at initiation, the probability of recurrence-free survival was 86.2% and 75.1% at weeks 26 and 52, respectively.
The absence of ustekinumab optimization was associated with upper odds of success (OR 2.74). “We can suppose in our present study that optimization of treatment was needed in severe refractory patients with no or insufficient response to ustekinumab. Thus, in these nonresponders, success was not achieved despite optimization.”
My take (partly borrowed from authors): “This large multicenter dedicated study adds substantial evidence to the growing literature on ustekinumab effectiveness in refractory CD.” For pCD, optimization of ustekinumab has a low likelihood of improving response.