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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A recent retrospective study (R Levy et al. J Pediatr 2019; 209: 233-5) analyzed the musculoskeletal presenting manifestations of pediatric inflammatory bowel disease (IBD).
In their cohort of 715 patients with IBD, 137 had arthritis and/or arthralgia. 28 of these 137 patients (3.9% of total cohort) had arthritis preceding the diagnosis of IBD and were eligible for this study. Only 23 had complete data and were compared with 46 children with arthritis due to JIA (n=21), FMF (n=7), and postinfectious arthritis (n=18).
- Patients with subsequent IBD diagnosis were more likely to have sacroiliac involvement (34.8% vs. 2.2%), more likely to have anemia (mean hgb 10.5 vs 12), more likely to have low albumin (mean 3.5 vs 4.3) and to have higher inflammatory markers (ESR 81 vs 46; CRP 6.6 vs 4.5 mg/dL)
- In patients with calprotectin levels, 5 of 6 were >300 mg/kg and one was borderline
- On direct questioning at time of IBD diagnosis, prolonged gastrointestinal symptoms (e.g. abdominal pain, diarrhea, weight loss, aphthous ulcers) were evident in 78%.
- 4 of the 23 (17.3%) were diagnosed with IBD during the primary investigation. Ultimately, Crohn’s diagnosis was established in 87% of the IBD group.
My take: This study is important for pediatricians and rheumatologists. ~4% of children presenting with arthritis have IBD. Careful interrogation for GI symptoms (and perianal exam) will avoid diagnostic delay in most patients as would a stool calprotectin. Features like sacroileitis, and abnormal labs should also increase the suspicion for IBD.
Briefly noted: In a study discussing pediatrician beliefs about JIA (MR Pavo, J de Inocencio, J Pediatr 2019; 209: 236-9) there is an important caveat for GI doctors:
“It is clear that booster vaccinations against measles, mumps, rubella, or varicella zoster virus, can be considered in patients receiving < 15 mg/m-squared/week of MTX [methotrexate]” (Pediatr Rheumatol Online J 2018; 16: 46).
Related blog post:
- IBD Update Feb 2019 -last entry shows study indicating that patients with IBD and arthritis were more likely to require biologics.
El Retiro Park, Madrid
A recent study (Limketkai BN, et al. Gut. 2019;doi:10.1136/gutjnl-2018-318074.) shows that the likelihood of eosinophilic esophagitis (EoE) is higher in patients with inflammatory bowel disease (IBD) and that the likelihood of IBD is higher in EoE patients.
Summary from Healio Gastroenterology –Risk for EoE higher in patients with IBD, and vice versa:
- Researchers conducted a prospective cohort analysis using the Truven MarketScan database from 2009 to 2016 to define the epidemiology and clinical implications of concurrent EoE and IBD diagnoses.
- Among their cohort comprising 134,013,536 individuals, the incidence of EoE was 23.1 per 100,000 person-years, CD was 51.2 and ulcerative colitis was 55.2.
- Compared with patients without either diagnosis, the risk for EoE was higher in patients with CD (IRR = 5.4, P < .01; prevalence ratio [PR] = 7.8, P < .01) and UC (IRR = 3.5, P < .01; PR = 5, P < .01). Meanwhile, the risk for IBD was higher among patients with EoE (CD: IRR = 5.7, P < .01; PR = 7.6, P < .01; UC: IRR = 3.4, P < .01; PR = 4.9, P < .01).
A recent retrospective study (J Breton et al. Inflamm Bowel Dis 2019; https://doi.org/10.1093/ibd/izz006) currently available online in advance of publication is likely to influence current practice in children with refractory inflammatory bowel disease (IBD). Thanks to Ben Gold for sharing this reference.
Link to abstract: Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease
Here are some of the details:
- There were 63 patients who met inclusion criteria.
- 27 (43%) with colonic (n=18) or ileocolonic (n=9) Crohn’s disease (CD)
- 23 (36.5%) with ulcerative colitis
- 13 (21% classified with IBD-U.
- 34 (54%) were corticosteroid-refractory or dependent
- 62/63 with previous or present loss of response or primary nonresponse to anti-tumor necrosis factor (anti-TNF) therapy
- 48 (76.2%) were receiving anti-TNF therapy at time of antibiotic initiation
- Of the 37 with available anti-TNF trough, 23 (62.%) were considered therapeutic (IFX ≥5, or ADA ≥7.5)
- Medical refractoriness “was defined by corticosteroid resistance, as shown by no or partial response to more than 7 days of hgih-dose corticosteroids (≥ 1 mg/kg/day prednisone equivalent) or primary nonresponse or loss of response to a biologic”
Antibiotic regimens: A=Amoxicillin, D =Doxycycline, M =Metronidazole, C= Ciprofloxacin, V= vancomycin. Antibiotic therapy was based on previous study which used ADM. A =50 mg/kg/day divided TID to max 500 mg/dose; D =4 mg/kg/day divided BID to max 100 mg/dose; M 15 mg/kg/day divided TID to max of 250 mg/dose. In children <8 yrs, C =20 mg/kg/day divided BID to max of 250 mg. Vancomycin 125 mg/dose QID in <8 y and 250 mg/dose QID in ≥8 yo could be added as a 4th drug and Gentamicin cold be substituted in those with a drug allergy.
- 45% ADM
- 8% ADMV
- 8% CMV
- 8% AMV
- 8% ACM
- 6% ADV
- 17% Other
Improvement with Regimen:
- Median PUCAI dropped from 55 at baseline to 10 (P<0.0001) by 3 weeks ± 1 week after antibiotic initiation
- 40 (63.5%) experienced a clinical response with a change in PUCAI of ≥20 points
- 25 (39.7%) entered clinical remission, including 6 who achieved corticosteroid-free remission
- Other markers of improvement: increased median hemoglobin (10.7–>11.6), Improved median CRP (1.1 –> 0), improved median ESR (38 –>21)
- Use of doxycycline (OR 0.25) and high PUCAI ≥ 65 (OR 0.2) were both associated with a much lower odds of clinical remission
- Among the 25 entering clinical remission, 13 (65%) had successful rescue of current anti-TNF therapy, 6 were transitioned to another biologic (vedolizumab or ustekinumab)
- No serious adverse drug-related toxicities were evident. No cases of Clostridium difficile. One patient had a vaginal yeast infection
- The authors interpret their findings as indicating that antibiotics could serve as an effective rescue therapy in some and potentially rescue anti-TNF therapy in patients with refractory disease.
- The discussion speculates that improvement is related to microbial modulation as dysbiosis “may play a causative role in perpetuating inflammation”
- In those placed on antibiotics, the authors state that “clinical response should be assessed frequently and therapy discontinued if no improvement is documented within 1 week”
Safety and Antibiotic Choice:
- While there were no safety signals evident in this study over 1 year, the long-term risks of using antibiotics is uncertain. For example, with ciprofloxacin, a fluoroquinolone, there is a well-recognized risk of permanent damage to tendons/joints (link to FDA update) and fluoroquniolones increase the risk of aortic tear/rupture. Because aortic rupture is rare, this increased risk represents a very low absolute risk.
- The authors indicate that doxycycline, used in 45%, had a much lower response rate. This makes the choice of antibiotic regimen uncertain –none of the other regimens were used in more than 8%.
- Given the retrospective nature, it is unclear whether some of the improvement could be related to additional time for the adjunctive/non-antibiotic treatments to work. Though, the authors found that the effect of antibiotics seemed to be independent of therapy optimization.
My take: This is an important study for children with limited treatment options in the setting of refractory disease and may act to salvage current anti-TNF treatment or facilitate a bridge to an alternative treatment. Though, the optimal antibiotic regimen in this setting is unclear.
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Disclaimer: These blog posts are for educational purposes only. Specific dosing of medications/diets (along with potential adverse effects) should be confirmed by prescribing physician/nutritionist. 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.
Heart-shaped Cactus, Joshua Tree National Park
Joshua Tree National Park. This image selected since this article discusses a ‘bridge’ therapy,
According to a recent study (Full Link: MR Noureldn, PDR Higgins et al. Aliment Pharmacol Ther. 2019;49:74–83. Incidence and predictors of new persistent opioid use following inflammatory bowel disease flares treated with oral corticosteroids), and with the limitation of using an insurance database –Key Findings:
- 5411 (35.8%) were opioid‐naïve patients (mean age 43.9 yrs) of which 35.0% developed persistent opioid use after the flare
- Factors associated with new persistent opioid use include a history of depression (hazard ratio [HR] 1.29, 95% confidence interval [CI] 1.13‐1.47), substance abuse (HR 1.36, 95% CI 1.2‐1.54), chronic obstructive pulmonary disease (COPD) (HR 1.17, 95% CI 1.04‐1.3), as well as, Crohn’s disease (HR 1.26, 95% CI 1.14‐1.4) or indeterminate colitis (HR 1.6, 95% CI 1.36‐1.88)
My take: As noted in previous blog (Increased Narcotic Usage in Pediatric Patients with IBD), opioid usage is an issue with pediatric IBD patients as well, particularly in those with associated depression and/or anxiety.
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A recent study (EJ Hoffenberg et al. J Pediatr 2018; 199: 99-105) examined the use of marijuana in 13-23 year age group with inflammatory bowel disease (IBD) at the Children’s Hospital for Colorado.
This relatively small study (n=99 — 62 with Crohn’s, 27 with ulcerative colitis, 10 with indeterminate colitis) found the following:
- Marijuana use was endorsed by 32 (32%) and that 9 used daily or almost-daily.
- Users were 10.7 times more likely to perceive low risk of harm (P<.001)
- 17 of 30 stated a medical reason for use (16 with physical pain)
- The most common route of use was smoking (83%)
- 80% of participants had inactive or mild disease
- There was no control (non-IBD) group to compare frequency of marijuana use
- Study performed in state with legalized recreational marijuana
My take: We know very little about how marijuana impacts IBD course and whether it is safe. This study indicates frequent use of marijuana in the 13-23 year age group. Thus, it is an issue that needs to be examined further.
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Three Sisters, Peaks near Canmore, Alberta
My view is that Clostridium difficile infection (CDI) in children with inflammatory bowel disease is often overdiagnosed due to detection of a carrier state in many when tested by PCR assays and the overlapping clinical features. This is particularly important when considering fecal microbiota transplantation (FMT) due to the potential risks of this treatment.
Recently, I had a letter to the editor (J Pediatr 2018; 199: 283) on this topic that was accepted:
The author’s reply suggested that their approach followed IDSA guidelines by checking CDI with PCR in those who were clinically-symptomatic. Yet, the IDSA guidelines (link here: IDSA C diff guidelines) do not focus on the issue of IBD flare-ups which cause identical symptoms. Expert IBD specialists have recommended the following for identifying CDI in patients with IBD:
“Start with enzyme immunoassay-based tests with a reflex to PCR test for discordant enzyme immunoassay results.” Rationale: “PCR is quite sensitive for the presence of toxigenic C difficile, it may increase the detection of asymptomatic colonization and shedding.” (K Rao, PDR Higgins. Inflamm Bowel Dis 2016; 22: 1744-54.)
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