“The boy noticed the colorization only when he urinated in the toilet at home and this phenomenon was most pronounced after the toilet had been cleaned.” He had a normal urinalysis. “Discoloration of urine by a chemical reaction between mesalamine and sodium hypochlorite bleach has been widely reported in online patient forums, we only found 2 related case reports.”
“Mesalamine and its metabolite, N-acetyl-5-aminosalicylic acid, have structural similarity to methyldopa, which is metabolized to melanin-like compounds. In an alkaline environment (the pH of bleach is 11–13), polymerization of these melanin-like metabolites causes a brownish/red discoloration of urine after methyldopa ingestion.”
In 2014, one of the posts on this blog addressed stopping anti-TNF therapy: Marriage, Divorce and Separation with Anti-TNF Therapy. My take at that time was “most patients are better off staying married to their anti-TNF therapy.”
Despite changes in therapeutic options, a recent study and editorial come to the same conclusion in 2022:
In the retrospective study, 78 patients with CD and 56 patients with UC underwent endoscopic reassessment. Key findings:
Mucosal healing (MH) was achieved by 32 patients with CD (41%) and 30 patients with UC (53.6%); 26 patients with CD (33.3%) and 22 patients with UC (39.3%) achieved histologic healing (HH)
Among 45 patients (n=24 CD, n=21 UC) with both MH & HH, anti-TNF therapy was stopped & patients received either an immunomodulatory or mesalamine. 76% of patients with CD had clinical relapse within 3 years and 17% within 1 year. Importantly, objective markers of relapse, including calprotectin and endoscopy were NOT performed; thus, this is certainly an underestimation of relapse rate and time to relapse.
In the commentary, the authors note the high rate of relapse in other studies with anti-TNF withdrawal (eg. STORI trial) and high rate of surgery in patients with perianal CD who stopped therapy. In the STORI trial, “the best outcomes [for infliximab withdrawal] were those with subtherapeutic infliximab trough levels, ie, those for whom infliximab was not responsible for maintaining their remission.”
The data are less certain for UC. The editorial notes that 85% of the 21 patients in the Scarallo study had limited left-sided colitis and only 17 were followed for at least 1 year. In adult studies on anti-TNF discontinuation with UC (Kennedy et al. Aliment Pharm Ther 2016; 43: 910-23 and Molander et al. Inflamm Bowel Dis 2014; 20: 1021-28), 42% and 35% relapsed within 12 months, whereas another small study (Farkas et al. World J Gastroenterol 2014; 20: 2995-3001) found 100% of patients on combination therapy who stopped anti-TNF agent had to restart anti-TNF therapy.
My take (from editorial): “The totality of the currently available evidence suggests that discontinuing anti-TNF medications in children with IBD is associated with a greatly increased risk of disease exacerbation, especially if the anti-TNF trough level was therapeutic.”
In this report, the authors describe nine patients with refractory microscopic colitis (median age 55 years) who were treated with vedolizumab.
Key findings:
Clinical response with induction in 9 (100%); time to >50% response ranged from 1 to 7 weeks with 5 patients responding within 2 weeks.
Sustained response with maintenance therapy in 6 (67%); duration of follow-up ranged from 1 month to 15 months. The three patients without response had symptom duration of 10 yrs, 12 yrs, and 25 yrs prior to institution of vedolizumab.
Only two patients had histologic follow-up. While both had clinical response, the patient with lymphocytic colitis had histologic resolution whereas a patient with collagenous colitis had histologic persistent.
My take: Given vedolizumab’s favorable safety profile, further studies (with endoscopic endpoints) of vedolizumab are needed to define its efficacy for microscopic colitis.
Key finding: The risk of serious infections was not different between vedolizumab and anti-TNF in the overall IBD cohort (HR, 0.95; 95% CI, 0·79-1.13), while the risk was decreased for vedolizumab users in patients with UC (HR, 0.68; 95% CI, 0.50-0.93), but not CD (HR, 1.10; 95% CI, 0.87-1.38)
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
On this website: “Four presentations/lectures were released at the Nutritional Therapy for IBD Virtual Booth that provide a comprehensive review and update of the latest information regarding the use of EEN and therapeutic diets in the management of IBD”
Why Do We Need Dietary Therapies for IBD
Presenter: Lindsey Albenberg, DO
Dr. Lindsey Albenberg, a clinician and researcher from Children’s Hospital of Philadelphia, describes the rapidly increasing incidence of IBD and its relationship to diet, microbiome and the immune system. She reviews the rationale and science supporting the use of dietary therapy to compliment drug therapy as an avenue to potentially achieve higher, more sustainable and possibly safer levels of remission long term in pediatric patients.
The Crohn’s Disease Exclusion Diet Updates: December 2021
Presenter: Rotem Sigall Boneh, RD. Rotem Sigall Boneh, RD, a primary researcher and developer of CDED, provides an overview of the accumulating data with CDED in combination with PEN, including the newly published results of adult data with important endoscopic findings and further shares real world experience and application of nutritional therapy.
IBD Anti-inflammatory Diet or IBD-AID: Proof of Concept
Presenter Ana Maldonado-Contreras, MSc, PhD. Dr. Ana Maldonado-Contreras, a lead researcher in IBD-AID explains the relationship between diet, microbiome and immune function with the design and rational of IBD-AID to manipulate the microbiome. She shares the recently published data of the impact of IBD-AID on the microbiome and cytokine levels specific to food components.
At the NTforIBD Nutritional Symposium prepared for NASPGHAN2021, Professor Day provides insight into the important role of EEN, an underutilized option to both induce remission and improve outcomes in complicated and peri-operative patients.
In this prospective study using the CCFA IBD Partners cohort, the authors examined fatigue symptoms with questionnaires (FACIT-F and MDI) at 3 timepoints over a 1 year period. There was likely a strong selection bias among participants (mean disease duration was 18 years) who chose to complete theses questionnaires. Key findings:
Persistent fatigue (at baseline and at 6 months) was the most common pattern, affecting two-thirds (65.8%) of patients
The strongest predictor of incident fatigue was sleep disturbance at baseline (odds ratio, 2.91.
Only 12.3% of those with fatigue at baseline had symptom resolution by 6 months. Resolution was more likely in patients with a diagnosis of ulcerative colitis, quiescent disease, and an absence of significant psychological comorbidity
My take: In those with fatigue, it is often persistent.
The authors retrospectively studied 7447 patients with dermatological conditions such as erythema nodosum (EN), pyoderma gangrenosum, Sweet’s syndrome, and aphthous stomatitis which can occur with inflammatory bowel disease (IBD) and are considered dermatological extraintestinal manifestations (D-EIMs).
Key findings:
131 (1.8%) subsequent IBD diagnoses in patients with D-EIMs compared with 65 (0.2%) in those without D-EIMs
Median time to IBD diagnosis was 205 days (IQR, 44-661 days) in those with D-EIMs
My take: The absolute risk if IBD is low in patients with D-EIMs but still increased 6-fold. This would probably be a good population to screen for IBD with a biomarker (eg. calprotectin)
J Shah et al. Inflamm Bowel Dis 2021; 27: 1832-1838. Ocular Manifestations of Inflammatory Bowel Disease Nice review: “ocular manifestations of IBD include keratopathy, episcleritis, scleritis, and uveitis and are among the most common extraintestinal manifestations.” Urgent referral to ophthalmology needed if deep eye pain that can awaken from sleep (?scleritis), if photosensitivity/blurry vision/headache (?anterior uveitis), or if floaters/decreased vision (?posterior uveitis)
Higher trough concentrations (TCs) (>10 mcg/mL) of anti-TNFa were not associated with higher rate of anti-TNFa-related adverse events in 135 patients & >1500 TC measurements
Out of the 30 patients who presented with elevated transaminases, 27 (90%) patients had normalized transaminases values by the end of the follow-up
Adverse events were noted in 68 of 135 patients (see below)
Forty-eight studies were included in the meta-analysis comprising 6963 patients. Key findings:
Biologic therapy in IBD pregnancies was associated with a pooled prevalence of 8% for early pregnancy loss, 9% for preterm birth, 0% for stillbirth, 8% for low birth weight, and 1% for congenital malformations.
These rates are comparable with those published in the general population.
Importantly, studies with newer biologics (eg. vedolizumab, ustekinumab) had small sample sizes. In addition, ongoing prospective multicenter registries are ongoing.
Endoscopic recurrence was 46% at 2 years (median time to recurrence: 10 months).
Histologic recurrence was present in 44% in endoscopic remission
At diagnosis and surgery, over a quarter met the criteria for growth failure.. Following surgery, height, weight and BMI z scores improved significantly both at 1 year and last followup
This multicenter, retrospective observational cohort study (2014-2017) studied the outcomes of 722 adults (n=454 vedolizumab (VDZ), n=268 TNF agents (165 IFX, 103 ADA). Key findings:
VDZ-treated patients were more likely to achieve clinical remission (hazard ratio [HR], 1.651; 95% confidence interval [CI], 1.229-2.217), steroid-free clinical remission (HR, 1.828; 95% CI, 1.135-2.944), and steroid-free deep remission (HR, 2.819; 95% CI, 1.496-5.310) than those treated with TNF antagonists
Safety: Overall, there were no statistically significant differences in the risk of serious adverse events (HR, 0.899; 95% CI, 0.502-1.612) or serious infections (HR, 1.235; 95% CI, 0.608-2.511) between VDZ-treated and TNF-antagonist−treated patients.
In TNF-antagonist−naïve patients, VDZ was less likely to be associated with serious adverse events than TNF antagonists (HR, 0.192; 95% CI, 0.049-0.754). Thus, among UC patients with no prior TNF exposure, there was nearly an 80% reduction in any serious adverse event (this difference could be related, at least in part, to patient selection/disease severity)
In TNF-exposed patients, VDZ was associated with a significant increased risk for serious infections (HR, 4.295).
The authors note that the clinical remission results are similar to a previous head-to-head study of VDZ vs ADA in which VDZ had OR 1.568 for achieving clinical remission. It should be noted that the potential conflict of interest list of the 36 authors is extensive.
My take: This article supports VDZ as a first-line option for UC and strengthens the argument that it should be the first biologic for most patients with UC.
Disclaimer: This blog, gutsandgrowth, assumes no responsibility for any use or operation of any method, product, instruction, concept or idea contained in the material herein or for any injury or damage to persons or property (whether products liability, negligence or otherwise) resulting from such use or operation. These blog posts are for educational purposes only. Specific dosing of medications (along with potential adverse effects) should be confirmed by prescribing physician. Because of rapid advances in the medical sciences, the gutsandgrowth blog cautions that independent verification should be made of diagnosis and drug dosages. The reader is solely responsible for the conduct of any suggested test or procedure. This content is not a substitute for medical advice, diagnosis or treatment provided by a qualified healthcare provider. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a condition.
This study utilized the Swedish nationwide health registry (2002-2017; n = 5767 with IBD) and controls from the general population (n= 58,418). One reason for this study is the increased frequency and changing patterns of immunosuppressive medications that are being used in pediatric IBD. Key findings:
672 serious infections (38.6/1000 person-years) occurred among the children with IBD compared with 778 serious infections in the control group (4.0/1000 person years; adjusted HR 9.46 ). HRs were increased for children with ulcerative colitis 8.48, Crohn’s disease 9.30, and IBD unclassified 12.1
Particularly high HRs were also seen in the first year of diagnosis with HR of 12.1 and n children with IBD undergoing surgery, HR 17.1. This 17-fold risk translates to an average of 6 per 100 children having a serious infection among those with operations.
340 of the 672 serious infections were gastrointestinal, including 34 due to Clostridium difficile
20 opportunistic infections were identified during 19,000 person-years
Potential risk factors for infection, besides medications, include malnutrition, chronic inflammation, impaired response to vaccination, and dysregulation of immune responses. A limitation of this study is ascertainment bias as families/patients with underlying disease may be more likely to seek medical attention for otherwise self-limited infections.
My take: This report confirms and quantitates daily clinical practice: children with IBD are more frequently hospitalized due to infections.
Methods: Randomized, parallel-group, open-label clinical trial including 458 adults (mean age, 44.8 years; 49.8% women) with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis (n=81), Crohn disease (n=66), or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospital
Key finding:
Sustained disease control without worsening was evident in 73.9% of pTDM group compared with 55.9% in standard infliximab group
Some limitations of this study:
The open-label study was not powered to detect the difference of pTDM in each of the six diseases
The therapeutic goal for maintenance infliximab was 3 to 8 mg/L, which is a little lower than current goals (ACG expert panel suggests a level of at least 5-10)
My take: This study supports recent expert guidance (see blog post below) on the benefit of pTDM as part of evidence-based care. It is likely that pTDM is even more important in children/teens due to growth.
Using national registries, the authors identified all patients with IBD (>15 years of age) and all cases of urolithiasis in Denmark during 1977-2018. Key findings:
2,549 (3%) of 75,236 IBD patients and 11,258 (2%) of 767,403 non-IBD individuals developed urolithiasis, resulting in a 2-fold increased risk of urolithiasis (HR, 2.27; 95% CI, 2.17-2.38) in patients with IBD
The authors note that a small risk of urolithiasis preceded the diagnosis of IBD: with OR, 1.42; 95% CI: 1.34-1.50 prior to diagnosis
After IBD diagnosis, risk of urolithiasis was associated with anti-TNF therapy and surgery (increased disease severity appears to be associated with increased risk). Anti-TNF therapy had a RR of 2.68 in patients with ulcerative colitis and a RR of 3.56 in patients with Crohn’s disease; for surgery, the RR were 3.14 and 2.74 respectively
One limitation is detection bias as patients with IBD may have more asymptomatic stones identified due to more frequent imaging
My take: This confirms an increased risk of urolithiaiss in patients with IBD and is a good reminder to consider this when patients present with severe abdominal pain/possible flare-up.
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