Category Archives: Uncategorized

“There is More to Life Than Death”

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This commentary helps explain some of the reasons for recent recommendations to drop PSA screening for prostate cancer and to stop mammograms for women ages 40 to 49 while at the same time showing how these decisions are not in fact ‘no-brainers.’ (NEJM 2012; 987-89).

With both decisions, the U.S. preventive services task force (USPSTF) focused on mortality data.  For prostate cancer, the pivotal trial was the U.S. Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) that showed no difference in mortality between a PSA-screened group and a control group.  Besides detailing a few limitations of the study, the authors note that separate epidemiologic data show a 75% decrease in men presenting with advanced prostate cancer since the introduction of PSA screening. Furthermore, a European study showed advanced cancers were 40% more likely in the control group as well.

Patients with more advanced prostate cancer are prone to bone pain and urinary obstruction; whereas, patients who undergo unnecessary surgery (b/c prostate cancer was not going to kill them) may develop incontinence and impotence.

For breast cancer, similarly, identifying smaller breast cancers may allow more conservative therapy. This has to be weighed against increased anxiety, discomfort, and biopsies for those with false-positive mammograms.

Conclusions:

“Basing decisions on the outcome of death ignores vital dimensions of life that are not easily quantified…It is neither ignorant nor irrational to question the wisdom of expert recommendations that are sweeping and generic.  There is more to life than death.”

On a side note, one of the authors (Jerome Groopman) has written several books.  My favorite of his: “The Measure of Our Days.”

Why call it botulinum?

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“Clostridium botulinum is a neurotoxigenic, anaerobic, gram-positive, spore-forming bacillus named after an outbreak of sausage poisoning in the late 1700s.” Botulus is latin for sausage.  Hence the name.

This and other facts about foodborne botulism are presented in a clinical problem-solving case (NEJM 2012; 367: 938-43).

Key information:

  • For foodborne botulism to develop neurotoxins must be absorbed from the gastrointestinal tract.
  • Fewer than 35 cases are reported annually in U.S.
  • Initial GI symptoms typically occur 12-72 hours after spore ingestion and can include constipation, cramps, vomiting, and less commonly diarrhea.
  • Biggest risk factors: home-canned foods or injecting black-tar heroin
  • Prolonged ventilatory support and antitoxin are cornerstones of treatment
  • Typical features: “Dozen D’s” dry mouth, diploplia, dilated pupils, droopy eyelids, droopy face, diminished gag reflex, dysphagia, dysphonia, difficulty lifting head, descending paralysis, and dyspnea.

To avoid being the next case report, if you like to can your own food, follow the guidelines in the link below:

National Center for Home Food Preservation | USDA Publications

More intriguing than helpful

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A recent study reports that a pH-impedance (pH-MII) may help identify children with allergen-induced gastroesophageal reflux disease (GERD) after exposure to cow’s milk (J Pediatr 2012; 161: 476-81).  The study population included 17 children (average age 14 months) with a clinical diagnosis of cow’s milk allergy (CMA) who had responded to an elemental diet.

Given the limitations of the study, it is hard to take seriously the conclusions of the authors that in “selected cases of children with CMA in whom GERD is suspected” pH-MII “should be considered as part of diagnostic workup.”

The limitations:

  • CMA diagnosed clinically based on response to dietary therapy
  • GERD diagnosed based on Infant GER Questionnaire, though authors acknowledge that “we are aware that no symptom or cluster of symptoms have been shown to reliably predict the diagnosis of GERD”
  • Statistically-significant findings only for weakly acidic reflux which was induced on second day after switching from elemental formula to cow’s milk
  • No endoscopic correlation of mucosal disease or exclusion of eosinophilic esophagitis
  • Small number of patients

I cannot see how obtaining a pH-MII study would offer a meaningful benefit to these patients; though, it is intriguing that one potential measure of clinical deterioration like increased weakly acid episodes can be detected when these patients are challenged with cow’s milk.

Some related blog entries:

Impedance recommendations from PIG

Gastroesophageal Reflux: I know it when I see it

Guidelines for Eosinophilic Esophagitis

NSAIDs and IBD

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While data has shown that nonsteroidal antiinflammatory drugs (NSAIDs) may worsen established IBD, whether these medications may serve as a trigger for IBD is less clear. One recent study indicates that NSAIDs may raise the risk of developing IBD (Ann Intern Med 2012; 156: 350-9).

This study examined the risk by using data from the Nurses Health Study which included 76,795 women.  Aspirin and NSAID use were self-reported.

Results:

  • “123 incident cases of CD and 117 cases of UC occurred over 18 years and 1,295,317 person-years of follow-up”
  • Frequent NSAIDs users (at least 15 days per month) had “increased risk for both CD (absolute difference in age-adjusted incidence, 6 cases per 100,000 person-years [95% CI, 0 to 13]; multivariate hazard ratio, 1.59 [CI, 0.99 to 2.56])”
  • And “UC (absolute difference, 7 cases per 100,000 person-years [CI, 1 to 12]; multivariate hazard ratio, 1.87 [CI, 1.16 to 2.99])”
  • There was no association with acetaminophen or aspirin within the same cohort.  This lessens the possibility of a false association; if subjects were treating GI symptoms, it is likely that an association would have been seen with all analgesics

The authors conclude that any absolute risk is low and therefore more important in understanding mechanism rather than in altering clinical use of these medications.

Link to abstract: Aspirin, nonsteroidal anti-inflammatory drug use, and risk for Crohn …

Additional NSAID references:

  • Gastroenterol 1966; 51: 430.  Sentinel article describing NSAID GI risk.
  • Gastroenterol 2008; 134: 1224.  Use of NSAIDs and risk prevention.
  • Clin Gastro & Hep 2007; 5: 1040. Long term effects of NSAIDs similar to COX-2 selective agents on small bowel mucosal damage (62% had abnormalities vs 50% of COX-2)
  • Clin Gastro & Hep 2006; 4: 1082 & 1090. Consensus on gastroprotection with NSAIDs.
  • Clin Gastro & Hep 2006; 4: 196.  NSAIDs worsen IBD.
  • Clin Gastro & Hep 2003; 1: 160.  Ileitis due to NSAIDs.

Adding Methotrexate to anti-TNF therapy

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While new therapies are emerging for inflammatory bowel disease as noted in recent blog entries on Vedolizumab and Tofacitinib, many patients have refractory disease and require management with available treatments.  One strategy in this situation has been to add methotrexate (Inflamm Bowel Dis 2012; 18: 1488-92).

This case series from the Mayo clinic reported their experience with 14 pediatric Crohn’s patients (10 males) who had methotrexate added to anti-TNF therapy.

Clinical remission was achieved in 50% (PCDAI <15) within 6 weeks with methotrexate (dose: 15 mg/meter squared –average dose 17.5mg SC weekly).  All patients received folate supplementation (1 mg daily). In this study, the average duration of methotrexate use was only 8.2 months & average followup was only 10 months.

Discussion notes that prior to methotrexate all patients had active disease despite anti-TNF therapy & most had received thiopurines. Most patients tolerated methotrexate. Four patients had Clostridium difficile infection; two cases were de novo.  Even after treatment of the infection, patients with Clostridium difficile were refractory to methotrexate treatment.

Of the initial 14 patients, two patients had severe nausea; this resulted in medication discontinuation in one patient and dose reduction in another patient.  No liver or kidney toxicity was identified.

Patients who did not respond to methotrexate, subsequent care including the following: three had surgery, one received tacrolimus/corticosteroids, one received natalizumab, one received certolizumab, and one received adalimumab/corticosteroids (while awaiting screening for certolizumab).

A prospective study of methotrexate is needed to confirm the its effectiveness in refractory Crohn’s and to determine long-term safety and efficacy.

Patient information on methotrexate (from my office website):  Methotrexate

Related blog entries:

Drug levels for inflammatory bowel disease

Methotrexate and liver toxicity

Additional methotrexate references:

-IBD 2011; 17: 2521. Methotrexate therapy: ~25% remission at 1yr, 16% at 2yrs.. n=93.
-JPGN 2011;53: 389. n=64. Supports use of zofran for 1st few months to prevent nausea.
-JPGN 2010; 51: 714. Use of MTX after thiopurines. n=27. 48% in remission at 6 months.
-JPGN 2009; 48: 526. Use in pediatric CD, n=25. 64% response

TPN cycling

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A randomized prospective study of early parenteral nutrition cycling was not helpful in reducing parenteral nutrition associated cholestasis (PNAC): J Pediatr 2012; 161: 229-33.

This study enrolled preterm infants <1250 g in the first five postnatal days to either cycled (n=34) or continuous parenteral nutrition (n=36).  Cholestasis was defined as direct bilirubin >2 mg/dL. The study indicated that intralipid 20% was administered in all patients over 18 hours; the exact amount is not clear, though in the cycled group, patients received 3 g/kg/day on postnatal day 3.9 ± 2.6.  All patients received dextrose over 24 hours; only the amino acid (TrophAmine) infusion varied: 20 hours compared with 24 hours.

  • PNAC in each group was nearly identical, 32% vs 31% as were bilirubin and transaminase values.
  • While the study was randomized, the cycled group did have more frequent late-onset sepsis 22 (65%) compared with 14 (39%) which reached statistical significance.
  • In addition, a trend towards more frequent non-surgical NEC in cyclical group was noted as well: 6 (18%) compared with 3 (8%).
  • PNAC was associated with days until full enteral nutrition/duration of parenteral nutrition and bronchopulmonary dysplasia.

The higher incidence of late-onset sepsis could have occurred randomly and affected the results; alternatively, the higher rate could reflect an increased risk of sepsis due to doubling the frequency of central line access.

This study was  only powered to detect a 25% difference between the groups; the authors estimate that a study with 290 patients would be needed in each group to identify a reduction of 10% in the incidence of PNAC.  As such, this study leaves open the possibility that cycled parenteral nutrition may be helpful in a smaller percentage, particularly if efforts are made to eliminate central line infections.  More promising efforts to minimized PNAC are noted in previous blog entries:

PNAC, PNALD, and IFAC

Optimizing lipids to minimize cholestasis

More on PNAC

Four advances for intestinal failure

Adalimumab for children with Crohn’s disease

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While adalimumab has been used in children with refractory Crohn’s disease, there has not been a lot of available data.  However, this situation has improved with the publication of the “IMAgINE 1” study (Hyams JS et al, Gastroenterology 2012; 143: 365-74).

This study enrolled 192 pediatric (6-17 yr-old) patients with moderate to severe Crohn’s disease; patients had PCDAI >30 and had failed conventional therapy with the exception of infliximab.  Approximately 45% in both groups had received prior treatment with infliximab.  The study started as an open-label induction followed by double-blind randomization into either a high-dose or low-dose maintenance phase.

Dosing:  For open label, patients >40 kg received 160 mg at week 0 and 80 mg at week 2.; patients <40 kg, received 80 mg at week 0 and 40 mg at week 2.

For maintenance, high dose was considered 40 mg every other week (eow) if >40 kg, and 20 mg eow if <40 kg.  Low dose was 20 mg and 10 mg respectively based on weight.

Results: 152 of 188 patients completed 26 week study period; 4 patients did not complete induction period.  At week 26, 63 patients (33.5%) were in clinical remission.  The high-dose remission response was 38.7% which was not statistically different from the 28.4% response in the low-dose group.

At week 52, there was a statistically improved response rate in the high-dose group 41.9% compared with low-dose group 28.4%; at the week 52 point, the remission rates were 33.3% compared with 23.2% respectively (p=0.1).  Among patients who were at least 13, it is noted that the overall CDAI clinical remission rate was 51% (week 26) and 36% (week 52) which are comparable to adult data from CHARM study.

Based on previous infliximab: Patients who had prior infliximab did not respond as favorably as infliximab-naive patients.  In the high dose group, the clinical remission at week 26 was 56.9% for infliximab-naive group compared to 16.7% for infliximab-experienced.  Similarly, the infliximab-naive response was higher, 68.6% compared with 47.6% for the infliximab-experienced.

Safety: “No new safety signals were detected.” Yet, 101 of 192 patients had adverse events during open label period, including 2 serious infections (which resolved & patients completed study).  Eight serious infections were noted during double-blind period.  Other safety problems included hepatic-related events in 9 of 188 patients, injection site reactions in 19 patients, hematologic adverse events in 8 patients, and 8 allergic reactions.  There were no reports of malignancy, congestive heart failure, lupus-like syndrome or demyelinating disease.

In both the high-dose and low-dose group, switching to weekly therapy instead of eow was allowed and commonly occurred: 48/95 in low-dose & 35/93 in high-dose.

Reasons for discontinuation: In both groups, drug discontinuation was frequent.  In the low-dose group, 37 patients stopped therapy.  In 18, this was due to lack of efficacy.  The other reasons included adverse effects in 10, protocol violation in 4, withdrew consent in 4, and lost to followup in 1.  In the high-dose group, 27  stopped therapy.  In 11, this was due to lack of efficacy; 12 had adverse effects, 2 withdrew consent, and 1 had protocol violation.

Another recent article (Inflamm Bowel Dis 2012; 18: 685-90) indicates that the annual risk of loss of response to adalimumab was 18% per year of followup.  This study involved 380 CD patients with an average age of 38 years.  This study also showed that there was a significant difference between patients naive to anti-TNF therapy and those who had prior anti-TNF therapy:  8% loss of response per year of followup compared with 22% respectively.

Related blog entries:

TNF-α antagonists and infections

CHOOSE TNF TRIAL

Disease modifying treatment in IBD

Only one chance to make first impression

TNF antagonists and UC

Adalimumab references:

  • -Gut 2011:  Gut doi:10.1136/gut.2010.221127. Use in induction of remission in UC. Reinisch W, et al. Adalimumab for induction of clinical remission in … – Gut – BMJ
  • -Aliment Pharmacol Ther 2010; 32: 1228-39. CHOICE trial. adalimumab effective in pts failing prior IFX.
  • -Gastroenterol 2009; 137: 1628. n=168.  71% & 67% of pts responded by weeks 4 & 12.  61% demonstrated sustained benefit. (in IFX failure pts). Of 156 pts, 65% needed to step up to 40mg weekly and 60 eventually stopped adalimumab due to loss of response.  Lower trough levels associated with loss of effectiveness & often with antibodies to adalimumab (present in 9.2% of pts).
  • -IBD 2011; 17: 2512.  n=50.  62% of pts develop skin reactions: eczema, acne-like dermatitis, psoriasis-like (6 of 50).  Adalimumab d/c’d in 22%.  Message -see dermatologist
  • -Lofberg et al. Am J Gastro 2008; 103: S418 (abstract 1069) Care study. -n=945. Humira at week 20 -remissions in 52% of pts naive to biologics, in 46% who prev responded to IFX & became intolerant, in 40% who prev responded to IFX and lost response, and 36% of pts with primary non-response to IFX.
  • -IBD 2008; 14: S1 Abrstarct 0002. Humira in TNF-naive patients with Crohn’s disease. Decreases hospitalizations. (12 month: 12.7% vs 20.3% in placebo group) Adult dosing: Induction 160mg, then 80mg in 2 weeks, then 40mg every 2 weeks.
  • -IBD 2008; 14: 1683. Response to adalimumab in 10 children.
  • -Gastro 2008; 135: 1493. n=778. mod-to severe Crohn had less hospitalizations (decreased ~60%) and surgery if Rx’d w Humira. 40mg eo week or qweek post 80/40 induction
  • -NEJM 2008; 359: 810. Use in pediatric JRA -helpful.
  • -JPGN 2008; 47: 19. n=15 pediatric patients. Complete or partial response in 64%.
  • -Gastro 2007; 132: 52. CHARM Trial. n=778. 40mg weekly c 47% response at week 26 (17% placebo) & 41% @ week 52 (12% placebo); works nearly as well in pts c prev inliximab as naive pts. Rapid onset ~c/in 2 weeks
  • -Clin Gastro & Hep 2006; 4: 1199-1213. Excellent review. Suggested dosing: 20mg every other week if 20-25kg, 25mg every other week if 25-30kg, 30mg every other week if 30-40kg, 35mg every other week if 40-55kg,  40mg every other week if >55kg, and increase to weekly dosing if needed
  • -JPGN 2008; 46: 1208, 226. pediatric case report and review of CHARM
  • -Gastro 2006; 130: 323-333. CLASSIC-I Trial, n=299. 36% 4-week response to 160mg/80mg week 0/subsequent week 2 (vs. 12% of placebo) All pts naive to anti-TNF Rx.

Adalimumab Injection Pain

  • –Suggestions from GI bulletin board. 1)you let the Humira Pen sit out for about 30 minutes prior to administering the medication, so that it appears clear and not foggy, that it greatly reduces pain at the site. 2) the pain disappeared after adding bicarbonate to the Humira. By trial and error, our nurse found that 0.15cc of bicarbonate is the minimum amount that yields a good effect.
  • -Lidocaine with adalimumab. Abstract reference: AF Ayala, Rosanne S.Groh, Brandt P.Robbins, Lisa M.Scalzi, Lizabeth Bingham, C. April TI The addition of injectable lidocaine to adalimumab results in decreased injection site pain and increased acceptance of therapy. 72nd Annual Scientific Meeting of the American-College-of-Rheumatology/43rd Annual Scientific Meeting of the Association-of-Rheumatology-Health-Professionals. CY OCT 24-29, 2008 CL San Francisco, CA. They used 0.2 ml 1% lidocaine into prefilled adalimumab syringe. We’ve tried this with a few patients and it seems to work well.
  • -Pt developed a “shot blocker” that is a bristle brush with a central hole for the syringe. The brush diffuses the pain from the Humira injection. Click the link below for a youtube video he created.
  • -http://www.youtube.com/watch?v=nfL95YRlTjY

Vedolizumab -another new IBD treatment

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Occasionally a parent will express concern that their child may run out of effective treatments for inflammatory bowel.  At this time, there are a limited number of effective therapies. If a patient develops reactions or antibodies to medications and/or does not have a clinical response, then the options become quite limited.

Against this backdrop, it is encouraging that new medical treatments are being tested, including Vedolizumab (Inflamm Bowel Dis 2012; 18: 1470-79).

The cited study reports the experience of using Vedolizumab in a randomized controlled phase 2 dose-ranging study in 46 patients (9 placebo, 37 vedolizumab).

Vedolizumab is “a gut-selective monoclonal antibody that antagonizes α4β7 integrin on select subsets of leukocytes binding to MAdCAM-1 on gut vascular endothelium.”  Many have considered vedolizumab to be similar to natalizumab, except it is considered  gut-specific and therefore should not increase the risk of progressive multifocal leukoencephalopathy (PML).  By altering the immune surveillance/lymphocyte tracking of the GI tract and not the brain, theoretically there should not be an increased risk of PML.

Another previous limitation of vedolizumab in small studies was the development of human antihuman antibodies (HAHA) –no joke!  HAHA occurred in up to 44% of patients in previous studies and were associated with reduced efficacy.  As a consequence, a new formulation of vedolizumab has been developed with presumably reduced  immunogenicity.

In the cited study, patients between 18-70 were recruited to receive one to three doses of vedolizumab (2, 6, or 10 mg/kg) or placebo.

Results:

  • Over 50% of vedolizumab-treated patients maintained a clinical response between days 29-253 whereas placebo response ranged between 22-33%.
  • This study was not powered for efficacy; however, the treated patients did have reduced fecal calprotectin.  At baseline, the calprotectin in the treatment groups averaged 405 μg/g and by day 113 had reduced to 54 μg/g.  In contrast, placebo group started with calprotectin of 310 μg/g and dropped to 192 μg/g during same time period.
  • HAHA were detected in 4 (11%)

According to a presentation at DDW (GEMINI I trial), more than 2500 patients have been treated in trials with vedolizumab.  None has developed PML. Encouraging results for efficacy (dosing 300mg IV q4weeks) were also noted; 1 year clinical remission noted in 45% of treated patients compared with 14% of placebo group. Digestive Disease Week 2012 – Vedolizumab Scores on Safety …)

Results of vedolizumab for Crohn’s disease are expected soon as well.

Related blog entries:

Quantifying Risk of PML with Natalizumab

Tofacitinib –a JAK Inhibitor for UC

CHOOSE TNF TRIAL

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While most physicians consider drug efficacy as the most important factor in choosing therapy, this is not always the determinant factor in patient choice.

The “CHOOSE TNF TRIAL” (Inflamm Bowel Dis 2012; 18: 1523-30) was a prospective survey of 100 adult patients with Crohn’s disease who were naive to anti-TNF therapy (infliximab, adalimumab, certolizumab).

Most important to patients:

  • Ease of use 69%
  • Time for therapy 34%
  • Time between applications 31%
  • Evidence for efficacy 19%
  • Fear of syringes 10%

Patient choice: Adalimumab preferred in 36%, certolizumab in 28%, and infliximab in 25%

While patient concerns need to be considered, others have shown that physician opinion is an important factor for patient decisions (J Rhemumatol 2008; 35: 618-24).  The discussion notes that “three anti-TNF drugs used in inflammatory bowel disease treatment have not been compared side-by-side in clinical trials.”  Thus far in pediatrics, infliximab is the only TNF approved for clinical use; as such, the other anti-TNF agents have been used primarily when infliximab loses effectiveness.

One drawback with injectable medications has been reduced adherence; up to 50% of patients fail to maintain regular injection interval; in addition, in patients who have had intravenous infusions (rather than patients who are naive) it is preferred over injections (Jay Popp, medical director of Janssen pharmaceuticals–personal communication).

As such, when patients receive infusions (eg. infliximab), closer followup and better adherence are more likely in comparison to injections.  This certainly improves efficacy.

Related blog entries:

TNF-α antagonists and infections

Disease modifying treatment in IBD

Only one chance to make first impression

Impedance recommendations from PIG

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The ESPGHAN Pediatric Impedance Group (PIG) has published a review/consensus statement on the use of pH-Impedance monitoring (MII-pH) in children (JPGN 2012; 55: 230-34).

Conclusions from this group:

  • MII-pH provides more information than conventional pH probe.  Whether this information will “inform prognosis, or predict response to therapy in pediatric patients has yet to be determined”
  • ‘As long as there is no effective medical therapy for weakly acid and nonacid reflux, the clinical relevance of MII-pH remains debatable’
  • “There are no data on the results of antireflux surgery based solely on the detection of weakly acid and nonacid reflux”
  • MII-pH is investigational technique needing standardization before routine diagnostic use can be recommended.
  • Major indications: need to identify weakly acid and nonacid reflux, persisting symptoms during antireflux treatment, use in identifying rumination syndrome, and research
  • Limitations of MII-pH: high cost, limited contribution to change in medical care, lack of evidence-based parameters for assessment of GER

Related blog entries:

Gastroesophageal Reflux: I know it when I see it

Treating reflux does not help asthma

The Medical Pendulum and Gastroesophageal Reflux