Methods: The authors linked prospectively collected data from national health care registries maintained for all adults in England on hospital attendances, imaging and endoscopic evaluations, surgical procedures, cancer, and deaths.
Over 10 years, we identified 284,560 incident cases of IBD nationwide; of these, 2588 patients developed PSC. This study excluded patients <18 years of age.
Development of PSC was associated with increased risk of death and CRC (hazard ratios [HRs], 3.20 and 2.43, respectively; P < .001) and a lower median age at CRC diagnosis (59 y vs 69 y without PSC; P < .001)
Compared to patients with IBD alone, patients with PSC-IBD had a 4-fold higher risk of CRC if they received a diagnosis of IBD at an age younger than 40 years
Development of PSC also increased risks of cholangiocarcinoma (HR, 28.46), hepatocellular carcinoma (HR, 21.00), pancreatic cancer (HR, 5.26), and gallbladder cancer (HR, 9.19) ( P < .001 for all)
The greatest difference in mortality between the PSC-IBD alone group vs the IBD alone group was for patients younger than 40 years
Patients with PSC-UC had >40% risk of colonic resection compared to patients with IBD alone (aHR 1.65)
My take: This study shows the impact the added diagnosis of PSC has for patients with IBD. One of the limitations in assessing outcomes is determining whether someone with IBD has PSC as there are a lot of patients with IBD who have asymptomatic changes in their biliary tree.
VDZ was initiated at median age of 16 years [IQR 15–18], 69% were male, 65% had large duct involvement, 19% had (Metavir F3/F4) fibrosis and 59% had ulcerative colitis.
Overall, there was a mild increase in median GGT after initiation of VDZ. Of 32 patients with abnormal GGT at baseline, 22% had a liver biochemical response (defined as GGT <50 or at least a 75% decline) after 9 to 12 months
For IBD, 32% achieved remission, 30% had a clinical response, and 38% had no response
In the discussion, the authors note that their findings are in agreement with three retrospective studies in adults which have shown that VDZ is not effective for PSC in patients with IBD.
My take: This study indicates that VDZ is not likely to help with PSC, though 62% of IBD patients had improvement in their GI disease.
EM Kim et al. Inflamm Bowel Dis 2020; 26: 1232-38.Mucosal Eosinophilia Is an Independent Predictor of Vedolizumab Efficacy in Inflammatory Bowel Diseases n=65 patients. In IBD cohort, colonic eosinophilia (340 +/- 156 vs 236 +/- 124) was associated with clinical non-response to vedolizumab (as was prior anti-TNF treatment). In those with ulcerative colitis, mean eosinophil count was 438 in nonresponders compared to 299 in responders. In those with Crohn’s disease, colonic biopsies showed a non-significant increase in eosinophil count in non-responders compared to responders: 352 vs. 232.
Crohn’s disease subjects with Pittsburgh Sleep Quality Index (PSQI) >5 more often had inflammatory phenotypes and reported increased benzodiazepine and psychiatric medication use. Crohn’s disease subjects with PSQI >5 also reported more night awakenings due to pain and bathroom use.
The PSQI correlated with HBI
PSQI >8 was predictive of surgery or hospitalization (hazards ratio 5.37; 95% confidence interval, 1.39-27.54).
My take: This study indicates that poor sleep is a marker for increased adverse outcomes/disease activity. It may be that sleep disturbance is due to increased disease activity or this may be a bidirectional issue in which poor sleep triggers more disease activity as well.
This retrospective study provides additional information on the observation that children with PSC often have subclinical disease; it is similar to a prospective study by the same group in 2018 (n=37): (prior blog post: Active Colitis More Likely in Children in Clinical Remission Who Have IBD and PSC) Key finding: Higher proportions of children with PSC-IBD had backwash ileitis, pancolitis, and rectal sparing, and more severe right-sided disease, than controls (P < .05). Conclusions: “Despite the mild clinical activity of IBD in patients with PSC, lack of symptoms does not always indicate lack of mucosal inflammation. Children with PSC-IBD have greater growth impairments compared with children with ulcerative colitis or IBD-unclassified.”
A Malian et al.Pedictors [sic] of Perianal Fistula Relapse in Crohn’s Disease. Inflamm Bowel Dis 2020; 26: 926-31. In this retrospective study with 137 patients, fistula relapse rates were not different in patients receiving infliximab or adalimumab (P = 0.66). In patients treated by anti-TNF at inclusion, discontinuation of anti-TNF therapy (odds ratio 3.49, P = 0.04), colonic location (OR 6.25, P = 0.01), and stricturing phenotype (odds ratio 4.39, P = 0.01) were independently associated with fistula relapse in multivariate analysis.
B Barberio et al. Matrix Metalloproteinase 3 Predicts Therapeutic Response in Inflammatory Bowel Disease Patients Treated with Infliximab. Inflamm Bowel Dis 2020; 26: 756-62. Retrospectively, 73 IBD patients who had received IFX for at least 1 year were enrolled: 35 patients were responders and 38 were nonresponders at 52 weeks…The MMP3 levels were similar at baseline (19.83 vs 17.92 ng/mL), but at postinduction, patients who failed to respond at 1 year had significantly higher levels than patients who responded (26.09 vs 8.68 ng/mL, P < 0.001); the difference was confirmed at week 52 (29.56 vs 11.48 ng/mL, P < 0.001)…The MMP3 serum determination may represent an early marker of response to infliximab.
A recent study (A Chandrakumar et al. J Pediatr 2019; 215: 144-51) followed 190 children with inflammatory bowel disease from 2011 to 2018 in a longitudinal population-based cohort in Manitoba and examined the development of primary sclerosing cholangitis (PSC). The diagnosis of PSC was made on discretion of the treating physician; thus, only a subset of patients underwent extensive evaluations for PSC.
9 developed PSC-UC (9/95) and overall 11 developed PSC-IBD (11/190)
Among children with PSC-UC, 8 had high GGT (>50) at baseline and only 1 had a normal GGT at baseline.
All UC patients who developed PSC were diagnosed withing 6 months of their UC diagnosis.
At baseline, 22 patients with UC had an elevated GGT and 73 had a normal GGT. Thus, about one-third of patients with an elevated GGT developed PSC (possibly more as all patients were not subjected to extensive testing)
My view: This study reinforces two concepts: 1) GGT is valuable as a screening test 2) PSC (often asymptomatic) is fairly common in UC and needs to be considered especially in the first year of diagnosis. What this study does not do is help us figure out what should be done about children with asymptomatic PSC as there are no proven therapies.
A recent clinical practice update (CL Bowlus et al. Clin Gastroenterol Hepatol 2019; 17: 2416-22) makes several recommendations on surveillance for hepatobiliary cancers in patients with primary sclerosing cholangitis (PSC).
I will highlight the most important recommendation for pediatric hepatologists:
Best practice advice 6: Surveillance for cholangiocarcinoma should not be performed in PSC patients with small-duct PSCs or those younger than age 20.
In the text, the authors note that “in pediatric PSC patients, cholangiocarcinoma is very rare, with only 8 of 781 (1%) …developing cholangiocarcinoma” (MR Deneau et al. Hepatology 2017; 66: 518-27)
Here are the other recommendations:
Best practice advice 1 Surveillance for cholangiocarcinoma and gallbladder cancer should be considered in all adult patients with PSC regardless of disease stage, especially in the first year after diagnosis and in patients with ulcerative colitis and those diagnosed at an older age.
Best practice advice 2 Surveillance for cholangiocarcinoma and gallbladder cancer should include imaging by ultrasound, computed tomography, or magnetic resonance imaging, with or without serum carbohydrate antigen 19-9, every 6 to 12 months
Best practice advice 3 Endoscopic retrograde cholangiopancreatography with brush cytology should not be used routinely for surveillance of cholangiocarcinomas in PSC.
Best practice advice 4 Cholangiocarcinomas should be investigated by endoscopic retrograde cholangiopancreatography with brush cytology with or without fluorescence in situ hybridization analysis and/or cholangioscopy in PSC patients with worsening clinical symptoms, worsening cholestasis, or a dominant stricture.
Best practice advice 5 Fine-needle aspiration of perihilar biliary strictures should be used with caution in PSC patients considered to be liver transplant candidates because of concerns for tumor seeding if the lesion is a cholangiocarcinoma.
Best practice advice 7 The decision to perform a cholecystectomy in PSC patients with a gallbladder polyp should be based on the size and growth of the polyp, as well as the clinical status of the patient, with the knowledge of the increased risk of gallbladder cancer in polyps greater than 8 mm.
Best practice advice 8 Surveillance for hepatocellular carcinoma in PSC patients with cirrhosis should include ultrasound, computed tomography, or magnetic resonance imaging, with or without α-fetoprotein every 6 months.
A large retrospective study (M Deneau, M Perito, A Ricciuto, N Gupta et al. J Pediatr 2019; 209: 92-6) examined the outcomes/response of ursodeoxycholic acid (UDCA) for pediatric primary sclerosing cholangitis (PSC).
“Within 10 years of diagnosis, 30% of children with PSC will require liver transplantation and 50% of children will develop complications, including biliary strictures and hypertension.”
Because UDCA has not been shown to improve survival (& may worsen outcomes), it is not recommended in adults by the AASLD.
In pediatrics, UDCA remains the most common treatment, used in more that 80% on long-term treatment
263 patients at 46 centers
Median age 12.1 years
UDCA median dose: 15 mg/kg/day
Normalization of GGT (<50 IU/L) occurred in 46% of patients in the first year after diagnosis
Patients with normalization was less likely among patients with Crohn’s disease and those with laboratory profiles indicative of more advanced hepatobiliary fibrosis (eg. lower platelet count, lower albumin, hyperbilirubinemia)
The 5-year survival with native liver was 99% in those who achieved normalization vs 77% in those who did not
Even in those without normalization, improvement in GGT was associated with better outcomes. “Those who had a reduction in GGT of >75% had nearly the same long-term survival as those with GGT<50 IU/L at 1 year.”
It has previously been shown that nearly “one-third of children who are UDCA-naive have spontaneous GGT normalization by 1 year.” Thus, the number to treat with UDCA to have one additional case of GGT normalization is four.
In a previous study, one-third of patients with GGT normalization on UDCA therapy for 1 year, maintained GGT <29 after withdrawal of UDCA for 12 weeks.
The authors note that “patients who do not achieve normalization could reasonably stop UDCA as they are likely not receiving clinical benefit.”
My take: This study shows that patients who have improvement/normalization of GGT with UDCA therapy have improved outcomes. The retrospective design of the study limits conclusions about whether UDCA therapy actually improves long-term outcomes, particularly since UDCA at higher doses has been associated with detrimental affects in adults with PSC.
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.
A recent study (O Olen et al. Gastroenterol 2019; 156: 614-22) was summarized quite succinctly by NEJM journal watch:
Using the Swedish National Patient Registry data, investigators identified 9442 incident cases of IBD diagnosed in patients under age 18 years from 1964 through 2014. Based on 139,000 person-years of follow-up, results were as follows:
There were 259 deaths among people with IBD (133 were from cancer and 54 from digestive disease).
The all-cause mortality rate in these patients was 2.1/1000 person-years, compared with 0.7 in matched reference individuals from the general population.
The average age at death was 61.7 compared with 63.9 years in the reference group.
The hazard ratio for death was 3.2 and was higher in those with ulcerative colitis (HR, 4.0), especially if they had concomitant primary sclerosing cholangitis (HR, 12.2), a first-degree relative with ulcerative colitis (HR, 8.3), or a history of surgery (HR, 4.6).
Mortality risks were similar when limited to the period after the introduction of biologics (2002–2014).
My take: This study found that having IBD diagnosed in childhood increased the risk of mortality (~1 extra death for every 700 patients followed for 1 year) especially in patients with concomitant PSC and in patients with severe ulcerative colitis. The study did not see an effect of the newest therapies but was underpowered to directly assess this effect.