A previous study has shown that low vitamin D levels improved with anti-TNF therapy for Crohn’s disease in the absence of supplemental vitamin D. Similarly, a recent study (MA Atkinson, MB Leonare, R Herskovitz, RN Baldassano, MR Denburg. JPGN 2018; 66: 90-4) showed improvement in iron metabolism with anti-TNF therapy.
In 40 children and adolescents with Crohn’s disease, the authors measured serum hepcidin-25 and hemoglobin at baseline and then 10 weeks after anti-TNF therapy.
- Median hepcidin concentrations decreased (27.9–>23.2 ng/mL) and mean hemoglobin increased (10.6–>10.9).
- Disease activity and markers of inflammation also decreased.
My take: This study shows that improvement in inflammation is associated with meaningful improvement in anemia. However, most patients will need additional treatment for anemia, particularly as anemia may be related to blood loss in addition to anemia of chronic disease/inflammation.
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A recent NASPGHAN clinical report (JB Splawski et al JPGN 2017; 65: 475-86) updates recommendations to lower the rate of postoperative recurrence in pediatric Crohn Disease (CD). In this report, after review of a number of studies, the authors provide a management algorithm (Figure 1). In addition, they review risk factors for surgery/postoperative recurrence in CD.
- “Endoscopic recurrence precedes clinical recurrence, and is a better predictor of the risk for future surgery.”
- “Anti-TNF agents appear to be the most effective treatment in preventing postoperative recurrence.” These agents “can be started as early as 4 weeks after surgery.”
- “Prophylactic treatment to prevent recurrence rather than treating after the disease recurs, appears to be more effective in preventing further surgery.”
- “Early postoperative surveillance for disease recurrence allows for a change in management to prevent complications that may lead to further surgery.” The authors note that fecal calprotectin (and lactoferrin) return to baseline around 2 months after surgery, and “monitoring disease activity postsurgery with these tests may help determine appropriate selection for more invasive testing such as endoscopy.”
My take: The authors emphasize that “whatever treatment is chosen, early surveillance for disease recurrence is clearly needed.” In addition, anti-TNF agents are most likely to lower risk of further surgery.
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A recent AGA perspectives issue provides two viewpoints on when to start/resume anti-TNF therapy after Crohn’s disease surgery:
Dr. Bressler states that he considers anti-TNF therapy for patients with ongoing immune dysfunction after surgery who are at high risk for recurrence. Attributes of high risk disease include the following:
- younger age (<30 years)
- two or more surgeries for penetrating disease.
His commentary indicates that a “‘wait and see’ approach is appropriate for most patients. He frequently will measure a calprotectin three months postoperatively and every three months and perform a colonoscopy typically 6-9 months postoperatively. Those with endoscopic recurrence will be placed on anti-TNF therapy.
Dr. Requiero states:
- The most effective way to prevent recurrence is to initiate an anti-TNF within four weeks of surgery. It has been my practice that patients at high risk for postoperative Crohn’s disease recurrence initiate anti-TNF shortly after they are discharged from the hospital.
- If a patient had been on an anti-TNF prior to the surgery, I will usually resume the same anti-TNF after the surgery. In these patients, I do not give a re-induction course unless they had not received the anti-TNF for more than three months prior to surgery.
- Concomitant therapy: “In the majority of patients, I treat with an anti-TNF, I will use a concomitant immunomodulator…One year after surgery, if there is no disease recurrence, I will decrease and often stop the immunomodulator. With the advent of therapeutic drug monitoring, I have a number of postoperative anti-TNF patients on monotherapy without an immunomodulator.
- [In] patients at moderate risk for postoperative recurrence… I perform an ileocolonoscopy six months postoperatively and, if there is evidence of endoscopic recurrence, I add an anti-TNF agent. After finding a high rate of recurrence in these patients, I am beginning to shift my practice to initiating anti-TNFs in this moderate-risk group as well.
My take: I tend to favor Dr. Reguieiro’s approach in my patient population.
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A recent study (A Yada et al. Inflamm Bowel Dis 2017; 23: 853-7) finds that insurance policies are not in compliance with expert guidelines. The authors reviewed 79 policies from the top insurance companies to examine their policies regarding anti-TNF agents, vedolizumab, and ustekinumab. These policies were compared with the American Gastroenterological Association (AGA) clinical pathway recommendations for ulcerative colitis (UC) and Crohn’s disease (CD).
- “90% of the policies required step-wise failure prior to starting anti-TNF for non-fistulizing CD.”
- “When choosing anti-TNF therapy, 26% of policies required the use of adalimumab as the first anti-TNF agent.”
- 98% of policies are inconsistent with AGA IBD guidelines
Discussion from authors:
- “The plans do not allow for treatment based on disease severity but rather dictate treatment based on the required failure of different drug classes.”
- “Only 2% of UC policies and 10% of CD policies allowed for early initiation of biologic therapy to reduce the risk of complications.”
- “The goal of medical management is to minimize the use of corticosteroids…However, the majority of the current policies…preclude this standard-of-care management.”
My take (from authors): “Most insurance companies do not comply with the current standard of care for treating IBD.” My expectation is that these problems will continue and/or worsen as the options for IBD treatment become more complex.
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JM Powers et al. J Pediatr 2017; 180: 212-6. This retrospective study details a protocol for using intravenous ferric carboxymaltose (FCM) (Injectafer) in children. This product has become available for adults in U.S. since June 2013; it had been available in Europe since 2009. In this retrospective study, 72 pediatric patients received FCM for iron deficiency anemia (off-label); there was a good safety profile and a good response with hemoglobin increasing from 9.1 to 12.3 (4-12 weeks post infusion). FCM is a relatively costly IV iron formulation, but can be given over 15 minutes.
L Peyrin-Biroulet et al. Clin Gastroenterol Hepatol 2017; 15: 25-36. This systemic review with more than 2800 patients showed that TNF antagonists were effective for extraintestinal manifestations of inflammatory bowel disease, including cutaneous disorders (eg.. pyoderma gangrenosum, erythema nodosum), hematologic problems (eg anemia), ocular disorders, and rheumatologic symptoms( eg. arthralgias/arthritis).
AE Mikolajczyk et al. Clin Gastroenterol Hepatol 2017; 15: 17-24. Useful review of the GI/Liver manifestations of autosomal-dominant polycystic kidney disease. “There is not a role for therapy [for the liver] in asymptomatic patients.” Other problems reviewed included pancreatic cysts, hernias, and diverticular disease. Related posts:
T Rajalahti et al. JPGN 2017; 64: e1-6. Among 455 patients <18 with Celiac disease, anemia was noted in 18%. This resolved in 92% after one year of a gluten-free diet. Anemia is associated with more severe histological and serological presentation. Related posts:
FL Cameron et al. JPGN 2017; 64: 47-55. This retrospective review of 93 children treated with infliximab and 28 children with adalimumab provides data on growth after anti-TNF therapy. This study shows that anti-TNF therapy is more likely to be associated with growth improvement when used at earlier stages of puberty.
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Another study (NA Kennedy et al. Aliment Pharmacol Ther 2016; 43: 910-23) has examined the issue of outcomes after anti-TNF therapy withdrawal among patients with inflammatory bowel disease.
This study included 166 UK patient cohort (117 with Crohn’s disease [median 31 yrs], 19 with ulcerative colitis [median 40 years]) as part of a retrospective observational study and a meta-analysis incorporating 11 further cohorts totalling 746 patients (624 with Crohn’s dissease, 122 with ulcerative colitis).
- In the UK cohort, relapse rates were 36% at year and 56% at 2 years for Crohn’s disease
- In the UK cohort, relapse rates were 42% at year and 47% at 2 years for ulcerative colitis
- Increased relapse rates were noted for those with a diagnosis prior to age 22 years (hazard ratio (HR) 2.78), calprotectin >50 mcg/g (HR 2.95).
- In meta-analysis, 1-year relapse rates were 39% for CD and 35% for UC/IBDU patients
- Retreatment with anti-TNF was successful in 88% for CD and 76% of UC/IBDU patients
To understand this study, it is important to note some of the study criteria. In the UK cohort, inclusion criteria required the patient to have had at least 12 months of ant-TNF therapy and be in corticosteroid-remission for at least 6 months. In addition, the relapse rate is likely to be underestimated due to using a definition of relapse that required either commencement of steroids, immunomodulator or anti-TNF therapy. The meta-anlaysis cohort studies also used clinical relapse rather than endoscopic or other objective markers.
My take: Relapse of clinical symptoms occur in about 40% after withdrawal in highly-selected groups who were doing well prior. Significantly higher rates of endoscopic relapse are likely. This study provides strong reasons for not interrupting therapy when it is working.
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It is well-recognized that Crohn’s disease is associated with delays in the onset and progression of puberty with the potential for stunted growth, impaired bone accrual, and diminished quality of life.
Now, a study (MD DeBoer et al. J Pediatr 2016; 171: 146-52) shows that initiation of anti-tumor necrosis factor α (anti-TNFα) treatment results in a rapid increase in sex hormone and gonadotropin levels.
In 72 adolescents, this observational study followed levels of sex hormones, gonadotropin levels, dual-energy x-ray absorptiometry, along with cytokine/inflammatory markers at initiation of anti-TNFα therapy, at 10 weeks and at 12 months.
- By week 10 , testosterone z scores in males increased from a median of -0.36 to 0.40 (P<0.05)
- By week 10 , estradiol z scores in females increased from a median of -0.35 to -0.02 (P<0.01)
My take (from the authors): This study suggests that “systemic inflammation suppresses gonadotropin-stimulated production of sex hormones” and that treatment of this inflammation with anti-TNFα agents allows rapid resumption normal production.
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