This “INPUT” (INcidence, Prevalence, Treatment and OUTome in Patients with IBD) study used 4 different data sets to provide “the clearest depiction to date of IBD [epidemiology] in the U.S.
Key findings:
The age-, sex- and insurance-standardized prevalence of IBD was 721 per 100,000 population. This equates to estimated 2.39 million Americans with IBD.
Sub-category prevalence: the prevalence of IBD per 100,000 population was 812 in White, 504 in Black, 403 in Asian, and 458 in Hispanic Americans.
My take: The prevalence of IBD continues to increase and the U.S. has one of the highest rates in the world.
In this prospective cohort with 369 patients, treatment included the following 113 infliximab, 133 vedolizumab, and 123 ustekinumab. All patients received standard dosing (eg. 5 mg/kg/dose every 8 weeks with infliximab). Per Table 1, dose of thiopurine was 100 mg (range 50-150, “using a 2:1 ratio of azathioprrine and mercaptopurine”); most patients received methotrexate at a dose of 12.5 mg. Key findings:
Infliximab levels were much improved in patients receiving combination therapy with either a thiopurine or methotrexate. In those patients receiving a thiopurine, a threshold of 6-TGN ≥146 was considered optimal.
Patients receiving combination therapy with methotrexate or a thiopurine and a 6-TGN concentration ≥146 pmol per 8 × 108 RBCs, and those with baseline infliximab level ≥12.3 μg/mL had a lower rate of secondary nonresponse when compared with those on monotherapy, thiopurine with 6-TGN <146 pmol per 8 × 108 RBCs, and baseline infliximab level <12.3 μg/mL (88.2 vs 11.8% [P = .04], 71.2 vs 45.5% [P = .04])
Ustekinumab and vedolizumab levels were NOT increased in patients receiving an immunomodulator
My take: This study reinforces the idea that there are pharmacokinetic benefits of combination therapy with infliximab (and extrapolated to other anti-TNF agents); there is a lack of benefit for most patients receiving ustekinumab and vedolizumab. Even with ustekinumab and vedolizumab, it is possible that patients with more severe disease may still benefit independent of pharmacokinetic effects on biologic agent.
Higher doses of infliximab monotherapy with therapeutic drug monitoring may achieve similar results as combination therapy. However, patients switching from one anti-TNF to another due to immunogenicity/antidrug antibodies are particularly likely to benefit from combination therapy. In addition, a recent ImproveCareNow study showed better outcomes for pediatric patients who received methotrexate with adalimumab (see below).
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.
In 2022, a study in JPGN showed that the rate of Hepatitis B virus (HBV) vaccination and immunity was similar in individuals with and without celiac disease (CD). In addition, there was no increased risk of HBV infection detected in CD patients. Thus, routinely checking hepatitis B status in all patients with CD was no longer justified. (See: Celiac Disease, Hepatitis B and Paul Harvey).
The same researchers in this study expand their findings to inflammatory bowel disease (IBD) and CD. In this retrospective cohort (2000-2019), using the Rochester Epidemiology Project which includes data from 162,847 residents. Key findings:
1264 incident cases of IBD/CD, only 6 HBV infections were diagnosed before the index date; 5 of the 6 had risk factors including IV drug use or living in endemic region.
No new HBV infection developed in any of 1258 patients with IBD/CD during a median follow-up of 9.4 years
The proportion of patients with HBV-protective titers (≥10 mIU/mL) decreased with time before plateauing, with protective titer rates of 45% at 5 up to 10 years and 41% at 15 up to 20 years after the last HBV vaccination. The control population with protective titers also decreased similarly with time though was consistently higher than the levels of patients with IBD/CD within 15 years after the last HBV vaccination
Context/Discussion:
Only 16% of vaccine recipients have measurable protective titers by age 18 years, according to the CDC.32
“Time-related waning of Ab levels to HBV after vaccination has unclear clinical significance. Although screening persons for HBV immunity by using anti-HBs titers is widely accepted, prior study results have shown that cellular immunity can also provide long-term HBV protection, even in the setting of nonprotective titers.”
Reactivation of HBV is a well-documented complication of immunosuppression in patients with IBD, and screening for dormant infection is of paramount importance at diagnosis
Limitations: the study population had a low rate of HBV acquisition; thus, the study findings may not apply to areas with higher risk for HBV.
My take: This study shows that treating low hepatitis B surface antibody levels with reimmunization is likely NOT needed in either the IBD or the celiac disease population, except perhaps in those at high risk. Checking HBV status prior to immunosuppressive therapy, though, is still needed to prevent reactivation of HBV in those at risk.
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 review article makes a number of useful points:
Almost all of the IBD medications (Anti-TNF, Vedolizumab, Ustekinumab, Tofacitinib, Ozanimod) should not be used in patients with untreated hepatitis B surface antigen positivity. Antiviral prophylaxis is recommended even patients with inactive disease (HBV DNA <2000 IU/mL/normal ALT) starting 2 weeks prior to immunosuppression up to 12 weeks after immunosuppression discontinuation.
Anti-TNF, Vedolizumab, and Ustekinumab can be safely used in patients with cirrhosis, tofacitinib requires a dose reduction, and ozanimod is NOT recommended
Autoimmune hepatitis may be triggered (rarely) by use of anti-TNFs; however, these agents have been uses off-label as a rescue therapy for AIH as well.
Anti-TNFs do not appear worsen liver function in PSC and may be associated with improvement in MASH (NASH)
Drug-induced liver injury (DILI) is common with anti-TNFs, often seen between the second and fifth doses. It is “generally transient and asymptomatic.” DILI may occur with ustekinumab, tofacitinib and ozanimod.
Tofacitinib may have a favorable effect on PSC. A retrospective study with 5 patients reported a 28% and 39% decrease respectively in total bilirubin and alkaline phosphatase within 6 months of starting therapy, A separate study with 42 patients showed a non-significant drop in alkaline phosphatase from 150 U/L to 132 U/L at 12 month followup.
The authors note that in patients with cirrhosis and posttransplantation, “vedolizumab and ustekinumab should be preferred due to their safer profile linked to infectious risk.”
“Patients with hepatobiliary disorders are often excluded from pivotal trials.” This contributes to a significant knowledge gap for patients with these comorbid conditions which are frequent in patients with IBD
My take: I don’t think I will be too popular if I hand out copies of this article to the kids I see later today –despite the useful advice. (This post was meant to be published on Halloween)
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.
The authors identifed 25 studies which met inclusion criteria. Key findings:
In the analysis of studies with 3-category outcomes (n = 13), the pooled frequencies of patients (n=646) with improved, unchanged, or aggravated IBD course after LT were 29.4%, 51.4% (, and 25.2%.
Subgroup analyses revealed that patients with ulcerative colitis (UC), younger age at LT, or shorter duration of follow-up were more likely to have an improved disease course.
In the analysis of studies with 2-category outcomes (n = 12), the pooled frequencies of patients (n=672) with improved/unchanged or aggravated IBD course were 73.6% and 24.1%, respectively
My take: Despite the intensification of immunosuppression, most often the course of IBD is unchanged in patients following a liver transplantation.
This study enrolled 297 children with Crohn’s disease starting anti-TNF therapy. Patients initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12–36 months.
Methotrexate dosing: For those in the active arm, oral methotrexate was administered with a weekly dose of 15 mg for children ≥40 kg, 12.5 mg for children 30 to <40 kg, and 10 mg for children 20 to <30 kg. All participants received pretreatment with ondansetron 4 mg (or placebo) to prevent nausea and folic acid (1 mg/d).
Key findings:
For treatment failure: among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55–1.56)
For treatment failure: among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19–0.81).
A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49–1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24–2.07).
In our study, only 38% of participants underwent colonoscopy during follow-up (41% had calprotectin measurement).
My thoughts on this study:
The COMMIT study Gastroenterol 2014; 146: 681-88 found similar findings with regard to infliximab (see blog post: Digging into the COMMIT Study). In this study, MTX with IFX was not superior to monotherapy but did result in fewer antibodies and better levels.
With IFX the benefits of combination therapy seem to be minimal in those with good therapeutic levels, S Lega et al. Inflamm Bowel Dis 2019; 25: 134-41, JF Colombel et al. Clin Gastroenterol Hepatol 2019; 17: 1525-32: (blog posts: Can Therapeutic Drug Monitoring with Monotherapy Achieve Similar Results as Combination Therapy for IBD?; Combination Therapy Study Points to Central Role of Adequate Drug Levels). In the discussion, the authors note that intensive therapeutic drug monitoring may contribute to better outcomes with infliximab compared to adalimumab. “The observed benefit of combination therapy among adalimumab users was demonstrated in the setting of standard of care TDM. Of note, anti-TNF dose or interval adjustment and TDM were more frequent in infliximab-treated patients than adalimumab-treated patients, likely due to ease of obtaining trough levels during infusions and more flexible dosing.”
My take: Given the increased difficulty monitoring the kids on adalimumab, they are probably better off on dual therapy. My suspicion, though, is that if they had optimized levels, the benefit of dual therapy is probably small and would mirror the findings with IFX.
This short article outlines the indications, availability, technical skills, cost-effectiveness and potential value of intestinal ultrasound (IUS). Some key points:
Goal: “IUS is used as a first-line investigation and can avoid or delay the need for more invasive and expensive testing (CT, MRI, or colonoscopy). Thus, costs are minimized and patient convenience is optimized”
Availability: “IUS is quite widespread in many European countries, but its uptake has been significantly less in other parts of the world, including the United States. Limitations to its use include the absence of standardized and reproducible protocols, lack of local expertise, and the perception that IUS is an operator-dependent tool, feasible only by highly experienced operators. In reality, however,…. studies specifically addressing sonographer variability demonstrate substantial agreement for color Doppler signals and almost perfect agreement for bowel-wall thickness, as the most relevant IUS parameter.”
Expertise: Trainees “have to perform at least 300 supervised ultrasound examinations in Italy and 400 in Germany to achieve full competency…It is believed that learners can achieve competency in IUS after approximately 200 supervised examinations, but it is important to acknowledge that a formal learning curve and the criteria for competency assessment have not yet been fully defined”
My take: Despite all the interest in this useful point-of-care tool, for IUS to become more widespread in the U.S. it will need to be incorporated in training programs. The threshold for competency is not achievable with a weekend seminar. It will be interesting to see how this test affects cost, management, and outcomes. Will it reduce or increase other cross sectional imaging testing? Is the information from IUS more useful than a calprotectin (stool biomarker) which could also be a point-of-care test?
In this prospective study (n=198), the authors examined lipid profile changes at week 10 in patients starting IBD medications: corticosteroids, thiopurines, methotrexate, anti-TNF-α agents, vedolizumab, ustekinumab, and tofacitinib.
Key findings:
Relative increases in total cholesterol, HDL-c, and LDL-c were significant after prednisone (+26%, +31%, +12%) and tofacitinib therapy (+20%, +25%, +26%), respectively
No changes were observed in other drug classes
Findings did not correlate with calprotectin or CRP values, likely indicating a direct medication effect
My take: Recent studies have provided some reassurance regarding tofacitinib and the risk of major adverse cardiovascular events (MACEs) (see posts below). Nevertheless, it seems prudent to monitor lipids in patients receiving JAK inhibitors.
The Oro Valley/Tucson Loop shared use bike path extends over 130 car free miles throughout unincorporated Pima County, Marana, Oro Valley, and Tucson. We managed a 40 mile bike trip.
SA Kahn et al. NEJM 2023; 388: 358-368. Case 3-2023: A 16-Year-Old Girl with Abdominal Pain and Bloody Diarrhea
This case report of a girl presenting with abdominal pain and diarrhea identifies a rare etiology, catastrophic antiphospholipid syndrome (CAPS). CAPS can result in ischemic colitis. This patient underwent a colonoscopy which was normal in rectum but then became abnormal in the sigmoid colon:
“CAPS is thought to result from the binding of antiphospholipid antibodies to cell surfaces, which activates endothelial cells, monocytes, and platelets and leads to inflammation, complement activation, and thrombosis. The formation of thrombi in patients with antiphospholipid antibodies is thought to be a multihit process.7 The presence of antiphospholipid antibodies in the blood is the first event, but the antibodies typically do not cause disease until another event occurs.”
Management of antiphospholipid antibodies: “Thrombotic disease manifestations are important in guiding therapy. For patients with antiphospholipid antibodies and no history of clotting, anticoagulation for primary thromboprophylaxis is generally not recommended…For patients with antiphospholipid antibodies and a history of unprovoked thrombosis (e.g., patients with APS), long-term thromboprophylaxis is recommended…For patients with more severe presentations — such as this patient, who had CAPS with thrombosis in multiple organs — treatment is more aggressive and involves targeting multiple steps within the CAPS cascade.”
From ChatGPT
My take: This 16 yo had a severe presentation and the case is a reminder that there are multiple reasons besides IBD for a teenager to have bloody diarrhea and abdominal pain.
gutsandgrowth 