An Insurance Company Doing the Right Thing (with Calprotectin)

“An Insurance Company Doing the Right Thing” –not The Onion headline this time.

Recently (April 7. 2019) United Healthcare put out a policy statement explicitly stating:

“Fecal measurement of calprotectin is proven and medically necessary for establishing the diagnosis or for management of the following:

  • Crohn’s Disease
  • Ulcerative Colitis”

Thanks to Kim Conn for identifying this policy.

The policy statement provides an in-depth rationale for why calprotectin is medically-indicated along with supporting recommendations from multiple GI societies and National Institute for Health and Care Excellence (NICE).  The policy statement includes a long list of references and would provide a strong argument in supporting calprotectin testing for all insurance providers.

Here’s the link: FECAL CALPROTECTIN TESTING United Healthcare.

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“Tofacitinib: A Jak of All Trades”

The clever title is derived from an editorial (KE Burke, AN Ananthakrishan. Clin Gastroenterol Hepatol 2019; 17: 1438-40) regarding three recent publications regarding Tofacitinib, a non-selective inhibitor of janus kinase (JAK) enzymes 1,2 and 3 which was FDA-approved in May 2018 for moderate to severe ulcerative colitis. This report was published prior to recent FDA warning regarding blood clots: FDA Warning on Tofacitinib

Two of the reports have been summarized previously on this blog:

The third study examines the safety of tofacitinib: W Sandborn et al. Clin Gastroenterol Hepatol 2019; 17: 1541-50

Methods: This study analyzed data from phase 2 and phase 3 trials with 1157 patients who had a median treatment of 1.4 years (1613 person-years).  More than three-fourths were receiving 10 mg BID.

Findings:

  • Serious infections were infrequent but there was a dose response relationship associated with herpes zoster infections.  At 10 mg BID,  the frequency was 5% whereas the rate was 1.5% in those receiving 5 mg BID and 0.5% in placebo-treated patients. This is likely related to interference of interferon production related to JAK inhibitor disruption.
  • Sandborn et al conclude that the “safety profile of tofacitinib for patients with UC appeared similar to that reported for patients with rheumatoid arthritis and for patients with UC treated with biologic agents, except for the higher incidence rate of herpes zoster infection.”

The editorial recommends NOT using tofacitinib for acute severe ulcerative colitis (ASUC); it “should be encouraged only in selected patients and preferably in the context of a research study.”  “Infliximab and cyclosporine [should be used] for steroid refractory UC;” however, they suggest that “one can consider initiating tofacitinib PRIOR to patients becoming steroid refractory.  “It could be used upfront on day 1.”

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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.

Combination Therapy Study Points to Central Role of Adequate Drug Levels

A recent study (JF Colombel et al. Clin Gastroenterol Hepatol 2019; 17: 1525-32) examines the effect of combination therapy and drug levels in achieving corticosteroid-free remission at week 26 (CSFR26).

The authors performed a post hoc analysis from 206 patients with Crohn’s disease (CD): 97 monotherapy with infliximab & 109 with combination infliximab/azathioprine

Key findings:

  • The proportions of patients achieving CSFR26 were not significantly greater among those receiving combination therapy vs monotherapy within the same serum infliximab concentrations
  • Mean trough infliximab concentrations in the combination therapy were higher than for monotherapy: 3.54 mcg/mL vs. 1.55 mcg/mL
  • Higher levels of antidrug antibodies were seen with monotherapy: 35.9% vs 8.3% of those with combination therapy.  Antidrug antibodies were detected only in those with lowest quartile of infliximab trough levels.

My take: This study indicates that combination therapy’s higher efficacy is due to  favorable pharmacokinetics rather than drug synergy.  If good infliximab trough levels can be achieved with infliximab monotherapy, this may obviate the need for combination therapy.  The uncertain factor is whether closer attention to trough levels will minimize the development of antidrug antibodies as effectively as the use of combination therapy.

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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.

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Red Meat for Dietary Cynics

A recent randomized study (L Albenberg et al. Gastroenterol 2019; 157: 128-36) examined whether a diet low in red or processed meats could reduce rates of Crohn’s disease (CD) flares.

Methods: Adults with CD were recruited into the FACES (Food and Crohn’s Disease Exacerbation Study) trial from 2013 to 2015. Participants were recruited from an internet-based cohort (n=15,600).  Eligible participants (consumed red meat at least once a week & in remission) were randomly assigned to high meat, n=118 (minimum of 2 servings per week) or low meat, n=96 (no more than 1 serving per month).  Outcomes were based on changes in sCDAI scores or need for treatment (new medication or surgery)

Key findings:

  • Any relapse occurred in 62% of participants in the high meat group compared to 42% in the low meat group.  This was not statistically significant.
  • At week 20, 18 participants in each arm had a stool calprotectin with the high meat group having a higher median: 74.5 mcg/g compared to 36.0 mcg/g (P=.13)
  • The high meat group did consume at least 2 servings per week in 98.5% of observed weeks compared to 18.8% of the low meat group.

Limitations:

  • Small number of diet participants
  • Study was not blinded and only a subset included more objective markers of response
  • Whether complete avoidance of red meat/processed meats would be more effective is unclear
  • In those in remission at baseline, it could take longer for the benefits of a dietary intervention to become evident

My take:  Limiting consumption of red and processed meats (particularly if meat is not lean) has been shown to have cardiovascular benefits.  While this study does not show a statistically-significant improvement in relapse rates in this cohort with Crohn’s disease, there are still strong arguments that a diet with increased fruits/vegetables and less red/processed meats would be beneficial.

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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.

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FDA Warning on Tofacitinib

From FDA: 7-26-19 FDA approves Boxed Warning about increased risk of blood clots and death with higher dose of arthritis and ulcerative colitis medicine tofacitinib (Xeljanz, Xeljanz XR)

An excerpt:

The U.S. Food and Drug Administration has approved new warnings about an increased risk of blood clots and of death with the 10 mg twice daily dose of tofacitinib (Xeljanz, Xeljanz XR), which is used in patients with ulcerative colitis…

Health care professionals should discontinue tofacitinib and promptly evaluate patients with symptoms of thrombosis. Counsel patients about the risks and advise them to seek medical attention immediately if they experience any unusual symptoms, including those of thrombosis listed above. Reserve tofacitinib to treat ulcerative colitis for patients who have failed or do not tolerate tumor necrosis factor (TNF) blockers. Avoid tofacitinib in patients who may have a higher risk of thrombosis. When treating ulcerative colitis, use tofacitinib at the lowest effective dose and limit the use of the 10 mg twice daily dosage to the shortest duration needed

  • 19 cases of blood clots in the lung out of 3,884 patient-years of follow-up in patients who received tofacitinib 10 mg twice daily, compared to 3 cases out of 3,982 patient-years in patients who received TNF blockers

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Depression Screening for Pediatric Patients with IBD

Recently, we had a morning conference to review depression screening for pediatric patients with IBD.  This lecture was led by Chelly Dykes, MD. Many of these slides were adapted from resources developed by the (ImproveCareNow) ICN Psychosocial Professionals group.

We have started depression screening with a subset of our patients and soon will start screening all children 13 years and older.  When this is working well, younger ages may be targeted as well.

Some of the key points:

  • Depression/anxiety are common, particularly in patients with inflammatory bowel disease
  • National rates of suicide have been increasing
  • Asking about suicide does not increase the risk of suicidality
  • We are fortunate to work closely with two psychologists, Bonney Reed-Knight and Jessica Buzenski

Some of the slides are listed below.

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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.

Ustekinumab in Pediatric Clinical Practice

A recent study (JR Dayan et al. JPGN 2019; 69: 61-67) provides some helpful insight into the use of ustekinumab.

Background: The authors conducted a retrospective review of 52 patients (73% younger than 18 years, 27% 18-21 years).

  • Median age at induction was 16.8 years.
  • 10 patients were biologic-naive; 42 had received at least one anti-TNF agent (18 had received two anti-TNFs).
  • 42 of the 52 patients had Crohn’s disease.
  • Of note, 64% of their patients had a normal baseline CRP and they defined “biomarker remission at 52 weeks” as having a normal CRP.  The high rate of normal baseline CRP likely indicates milder disease than many other refractory populations; though nearly half of the patients with Crohn’s disease were receiving steroids when ustekinumab was initiated.
  • Steroid-free remission was defined by Harvey Bradshaw Index ≤4 or partial Mayo Score <2 and off steroids for >4 weeks.

Dosing: 47 (90%) received induction with ustekinumab IV (260 mg if <55 kg, 390 mg if 55-85 kg, 520 mg if >85 kg) followed by 90 mg subcutaneous injections every 8 weeks

Key findings:

  • 75% of patients continued to receive ustekinumab at 52 weeks.
  • 50% of bio-exposed patients were in steroid-free remission
  • 90% of bio-naive were in steroid-free remission
  • 57% received a dose escalation (increased frequency due to inadequate clinical response); such that at 52 weeks, 12 were receiving q4 weeks, 9 were receiving q6-7 weeks, and 15 continued with q8 weeks.
  • With a median f/u of 18 months, the authors reported few serious adverse events: two patients had an anaphylactoid reaction with IV induction (Rx with steroids and epinephrine). One of these two went on to experience arthralgias, fatigue and headaches with maintenance injection and treatment was discontinued. One patient experienced “self-limited paresthesia of bilateral lower extremities at 16 months on therapy” (CHOP experience with 22 patients reported one case of transverse myelitis: #NASPGHAN17 More Abstracts)

Discussion:

  • The authors note low immunogeiecity of ustekinumab and “suggest that ustekinumab monotherapy is possible and preferable in children”
  • Limitations: Lack of better objective markers for response to treatment

My take: This data indicates that ustekinumab therapy was associated with clinical remission in 50% of patients who had received anti-TNF therapy and had higher response in a small sample of biologically-naive patients.  More experience is needed to confirm drug safety with long-term usage

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