Category Archives: inflammatory bowel disease

Immune-Mediated Reactions to Anti-TNFs and What to Do About Them

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A recent review article (Feuerstein JD et al. Inflamm Bowel Dis 2015; 21: 1176-86) serves as a useful reference regarding immune-mediated reactions to anti-tumor necrosis factor (anti-TNF) medications used in inflammatory bowel disease (IBD).

Background:

  • All anti-TNF agents induce antidrug antibodies (ADAs).
  • With regard to infliximab (IFX) which has the most literature, it is well-recognized that combination therapy with an immunomodulator reduces the risk of antibodies to infliximab (ATIs).  For example, in the SONIC study, ATIs were noted in 0.9% of those with combination therapy compared with 14.6% of those receiving monotherapy with IFX.  With the UC-SUCCESS, the rates were 19% and 3% respectively.

Acute Infusion Reactions -Key points:

  • Acute infusion reactions (IRs) are more common in patients with ADAs.  IRs can be categorized as acute (w/in 24h) and chronic (2-14 d after infusion).
  • Acute IRs can be mild (dizziness, flushing, nausea, palpitation), moderate (chest pain, hypertension [SBP increase of more than 20], hypotension, fevers urticaria, mild dyspnea, chills, rash) or severe (severe hypertensions [SBP increase of more than 40] , severe hypotension, significant dyspnea with brochospasm, stridor, and rigors)
  • The authors provide a treatment algorithm (Figure 1) based on severity of acute IR.  All reactions are initially treated by stopping infusion, but many can be restarted at a low rate after administration of acetaminophen (mild & moderate), normal saline (mild & moderate), diphenhydramine (moderate), and possibly hydrocortisone (if needed in moderate cases).  While the algorithm suggests the possibility of restarting infusion reaction in severe cases without anaphylaxis, if this is considered, it may be worthwhile to attempt in a hospital setting.
  • Typically if infusions are restarted, the rates are 10 mL/hr x 15 minutes –>20 mL/hr x 15 minutes–> 40 mL/hr x 15 minutes –>80 mL/hr x 15 minutes –>100 mL/hr x 15 minutes–>125 mL/hr until completion.
  • Following an IR, the authors recommend checking for ATIs and for IFX level.
  • Prophylaxis for mild IRs includes the use of acetaminophen and antihistamines (2nd generation antihistamine daily for 5 days prior or first generation antihistamine an hour prior to infusion).  In addition, the infusion should be started at 10 mL/hr
  • Prophylaxis for moderate IRs includes the use of acetaminophen and antihistamines and steroids (prednisone 50 mg q12 hr x 3 doses prior or hydrocortisone 100 mg (or equivalent) 20 minutes prior to infusion).  In addition, the infusion should be started at 10 mL/hr
  • The authors recommend against premedication in those who have not had IRs. Use of premedication may cause a paradoxical increase in IRs due to symptoms induced by the antihistamine.

Autoimmune Complications:

  • Autoantibodies: anti-nuclear antibody (ANA), anti-double-stranded DNA antibody (anti-dsDNA), anti-cardiolipin antibody, antihistone antibody
  • Drug-Induced Lupus Erythematosus (DILE) -“the most frequently presenting symptoms, seen in 90% of cases, is symmetric arthralgias.”  Systemic involvement of the kidneys or central nervous system is rare. Treatment is cessation of the offending medication.
  • Vasculitis -likely due to the development of circulating immune complexes that deposits into smaller capillaries–>result in a type III hypersensitivity reaction.  The most common manifestation would be palpable purpura due to a leukocytoclastic vasculitis.
  • While autoimmune complications can be a class effect, many patients have been able to switch to a different anti-TNF.

Dermatologic Complications:

The authors review both anti-TNF induced psoriasis and eczema.  Treatment should be in conjunction with dermatology.  For psoriasis that involves >5% of body surface area, this could require changing to a different anti-TNF or a different drug class.  For severe cases, “anti-TNF therapy should be discontinued.”

Related blog posts:

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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Stopping Infliximab –What Happens Next?

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A recent retrospective single-center study (Papmichael K et al. Clin Gastroenterol Hepatol 2015; 13: 1103-10) of 100 patients with Crohn’s disease examined what happens to patients who discontinued infliximab therapy upon clinical remission.  The study used a medical database in Belgium.  The authors defined sustained clinical remission (SCR) as “maintenance of disease remission, without escalation in medical therapy or CD-related surgeries, until the end of the follow-up period, which was a median period of approximately 10 years.” 84 patients continued on immunomodulator therapy.

Key findings:

  • 52 (52%) had SCR.
  • Complete mucosal healing, lower infliximab trough concentrations, and serum positivity for vascular cell adhesion molecule-1 were factors associated with SCR.

Limitations: SCR was based on physician global assessment which may underestimate relapse rates and endoscopic data at the time of infliximab discontinuation was available in only a small subgroup.

Bottomline: In this small study, half of the patients did well clinically for a long time after stopping infliximab (most remained on immunomodulator therapy).  However, given the insidious nature of Crohn’s disease, careful monitoring before and after stopping infliximab is worthwhile.  In addition, other studies have demonstrated higher relapse rates.

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Optimal Dose of Thiopurine When Used for Combination Therapy

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To improve long-term outcomes and response in patients with inflammatory bowel disease, many experts advocate the use of combination therapy (thiopurine with anti-tumor necrosis factor).  Thiopurine cotherapy resulted in higher response rates in pivotal studies (eg. SONIC, UC Success), likely due to lower rates of antidrug antibody (ADA) and higher serum levels of biologic agents (e.g. infliximab).  To achieve these advantages, it is not clear whether a lower dose of a thiopurine may be similarly effective as a higher dose.  If a lower dose could result in a similar effect, it would likely result in fewer adverse effects.

A recent study (Yarur AJ, et al. Clin Gastroenterol Hepatol 2015; 13: 1118-24) provide some data to address the issue of optimal dosing of thiopurines.  The authors performed a cross-sectional study of 72 patients receiving infliximab (IFX) and a thiopurine.

Key findings:

  • The thiopurine metabolite 6-thioguanine (6-TG) that “best predicted a higher level of infliximab was 125 pmol/8 x 10 to the 8th RBCs.”
  • Only 8 patients (11%) had detectable antibodies to infliximab (ATI)
  • Patients with 6-TG <125 were more likely to have ATI (OR 1.3)
  • Higher 6-TG levels did not confer additional benefit

This study had many limitations including the small number of patients and the cross sectional design.  In addition, the patients may not be representative of typical patients; more than 50% were in endoscopic remission. A randomized controlled trial with larger number of patients is needed for a more definitive answer.

Take-home message: (from authors); “6-TGN metabolite levels rather than weight-based dosing may assist clinicians in optimizing treatment when using thiopurines in combination with IFX…lower target 6-TGN levels (125-176 pmol/8 x 10 to the 8th RBCs) may be adequate to maximize IFX levels and reduce immunogenicity while potentially minimizing toxicity.”

Briefly noted:

Ananthakrishnan AN et al. Clin Gastroenterol Hepatol 2015; 13: 1197-1200.  In this prospective study with 1659 patients with Crohn’s disease (CD) and 946 patients with ulcerative colitis, the authors found wide variation among the 7 participating academic centers, particularly with regard to CD treatment.  Comparing the site with the lowest usage to the highest usage, for CD:

  • Oral mesalamine 13% vs. 46%
  • Immunomodulator use 16% vs. 56%
  • Anti-TNF use 31% vs 60%
  • Combination therapy 8% vs 32%
  • Immunomodulator-naive anti-TNF use 10% vs. 17%
  • Surgery 32% vs 55%

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Cumberland Island

New Target Drug Levels in Inflammatory Bowel Disease

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According to a recent review (Vaughn BP, Sandborn WJ, Cheifetz AS. Inflamm Bowel Dis 2015; 21: 1435-42), higher target levels of infliximab should be considered.

After reviewing the relevant studies which are summarized in Table 1, the authors state that in their experience infliximab (IFX) levels of 5 to 10 mcg/mL are desirable.  Using this standard, they note in a retrospective review that proactive testing identifies only 29% of patients in this range.

Similarly, the TAXIT study (Casteele NV et al. Gastroenterol 2015; 148: 1320-29) identified 44% of patients with a trough concentration of 3-7 mcg/mL at baseline screening.  In this study, after achieving an adequate trough concentration, they found that patients had ~70% clinical remission at 1 year.  TAXIT acronym = the Trough Concentration Adapted Infliximab Treatment trial.  The TAXIT study was a 1-year randomized control trial with 263 adults (178 with CD and 85 with UC).

Recommendations from this review:

  • When therapeutic drug monitoring is used to react to symptomatic patients (Figure 1), if they test negative for antibodies to infliximab (ATIs) and have a low IFX level, then increasing the dose is recommended.  In those with therapeutic IFX and negative ATIs, then consider change in drug class or surgery (rather than dose escalation).
  • When therapeutic drug monitoring is used to react to symptomatic patients, if they test positive for ATIs, if there is a low level ATI (<15 mcg/mL for the referenced assay), then increasing the dose is recommended, otherwise consider change in drug class or surgery (rather than dose escalation).
  • For proactive monitoring, if negative ATI, and IFX trough level is >10 mcg/mL consider extending interval.  If the IFX level is low, increase dose.  If IFX is therapeutic, continue same dose and consider re-check in 6-12 months.
  • For proactive monitoring (Figure 3), if positive ATI, the authors recommend increasing dose if faced with low level ATI and consider change in drug class or surgery (rather than dose escalation). [If someone is doing well, I would not agree with this recommendation.  I would not stop a therapy based on a single blood test.]

One more useful point:

The authors note that combination therapy improves IFX levels and lessens the likelihood of ATIs.  “Current evidence suggests that combination of an anti-TNF with an immunomodulator is the most efficacious treatment for new-onset IBD.”  They speculate that proactive monitoring may allow IFX monotherapy without the need for combination therapy or allow de-escalation of combination therapy.

Bottomline: Consider a higher infliximab target level (5-10 mcg/mL) and using proactive monitoring to achieve higher remission rates.

Related blog posts:

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Cumberland Island

Briefly noted:

Casen C, et al. Aliment Pharmacol There 2015; 42: 71-83. (Thanks to Ben Gold for this reference). After studying the stool of 165 healthy controls, the authors used 54 DNA probes targeting >300 bacteria.  This genetic analysis-map dysbiosis test, subsequently analyzed 330 more patients; it confirmed dysbiosis in 73% of IBS patients, 70% of treatment-naive IBD patients and 80% of IBD patients in remission compared with 16% of healthy individuals.  Take-home point: Ultimately stool analysis could lead to more accurate evaluation and monitoring of individuals with suspected IBS or IBD.

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.

 

What “Treat-to-Target” Could Look Like in Crohn’s Management

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A recent study (treat to target full text -Bouguen G et al. Clin Gastroenterol Hepatol 2015; 13: 1042-50) proposes  a “new paradigm for the management of Crohn’s disease.”  The concept of treating-to-target has been discussed in several previous blogs:

The concern with the traditional management has been ongoing damage to the bowel in many patients and lack of optimizing long-term outcomes.  The authors in the report make the following points:

  • Only 10% of Crohn’s disease (CD) patients experience prolonged remission of symptoms
  • Even asymptomatic patients often have evidence of active inflammation on endoscopy
  • The majority of patients will require surgery
  • Two big obstacles: delay in initiation of highly effective therapy (eg. combined biologic/immunosuppressant) and underestimation of disease activity due to poor correlation of symptoms to actual disease activity

While the fact that the majority of patients are at risk, some populations are at increased risk including the following:

  • those who smoke cigarettes
  • patients younger than 40 years at diagnosis
  • stricturing or penetrating disease
  • need for surgery
  • inability to wean corticosteroids
  • deep ulcerations on endoscopy

However, the authors note that “the lack of adequate data in this area of research makes risk stratification very difficult in clinical practice.” The authors review several studies:

  • ACCENT-I
  • Step-Up Top-Down trial
  • IBSEN population-based cohort study
  • SONIC
  • The Leuven cohort study
  • EXTEND trial

The data from these studies is used to base their argument of pursuing mucosal healing/more aggressive treatment, though they acknowledge that one risk is potentially subjecting some patients to overtreatment.  The review indicates that mucosal healing (MH) is defined endoscopically as “the disappearance of ulceration” and that endoscopy is the tool for testing for MH for the near-term, but that other markers including MRE and surrogate biomarkers may be useful alternatives.

The authors’ Table 1 list their proposed recommendations for CD, modeled after similar recommendations for Rheumatoid Arthritis.  The Four Key points:

  1. The physician and patient need to agree on the treatment target strategy
  2. The primary target for treatment of CD should be absence of endoscopic ulceration
  3. The use of both clinical symptoms and objective measures of inflammation (endoscopic or imaging) is required in routine clinical practice to guide treatment decisions
  4. Until the desired treatment target is reached, MH should be assessed every 6 months until the disappearance of ulceration and every 1-2 years thereafter.  Drug therapy should be adjusted accordingly.

Limitations on this strategy:

  • Cost of assessment–both endoscopy and MRE are expensive
  • Cost of therapies
  • While MH can be achieved in a higher percentage of patients, there are some patients who will not respond to any of the currently available therapies
  • Risk of therapies.  Some patients will develop adverse effects from the available therapies which will limit their therapeutic options.
  • This proposed strategy has very limited data in clinical practice

Take-home message from the authors: The “natural history” is not likely to improve unless the overall, symptom-based, therapeutic strategy for CD is changed.

Atlanta Zoo, Wreathed Hornbill

Atlanta Zoo, Wreathed Hornbill

 

 

Money Matters in Pediatric Inflammatory Bowel Disease

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A very pragmatic article (Sin AT et al. Inflamm Bowel Dis 2015; 21: 1368-77) describes the out-of-pocket cost burden in pediatric inflammatory bowel disease (IBD). For anyone who lives on planet earth, how much a procedure or treatment costs weighs very heavily on many decisions.  This is particularly relevant in pediatric IBD.

In a cross-sectional cohort analysis, the researches collected data with surveys from 150 parents of children with IBD (67 Crohn’s disease, 83 Ulcerative colitis).  The median patient age was 14 years.

Findings:

  • Annually, out-of-pocket expenses were >$5000 in 5.3%, >$1000 in 28.6%, and >%500 in 63.6%.
  • Increased expenditures were derived from the following: emergency department visits with 36% having had an ED visit in past year, procedures/testing with 20% who spent >$2000, and from treatments (medications/diet).  10.7% reported missing medications due to cost.
  • “Families with household incomes between $50,000-100,000 had a statistically-significant probability (80.6%) of higher annual OOP costs than families with lower income…or higher income.”
  • Not surprisingly, patients with IBD “who have relapsing or uncontrolled IBD states are particularly at risk to require acute care services, which represent high OOP costs for families.”
  • The authors also describe missed workdays and lost wages as another financial burden.

Take-home message: This study helps quantitate the out-of-pocket expenses and financial burden that families face when they have a child with IBD.  In some patients, improved control of IBD will lower these expenses by decreasing costs from emergency department visits, office visits, and hospitalizations.

Cumberland Island

Cumberland Island

PCDAI -Not Good Enough

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Two articles reinforce the view that the pediatric Crohn’s Disease activity index (PCDAI) is not good enough to rely on for research and for clinical practice.

  • Sun H et al. JPGN 2015; 60: 729-36
  • Vubin G, Peter L. Inflamm Bowel Dis 2015; 21: 1386-91

The first article is a review of the PCDAI and its derivatives (abbreviated, short, modified, and weighted) as well as the Harvey-Bradshaw Index (HBI). Key points:

  • There was an “absence of evidence demonstrating correlation with clinically relevant inflammation.”
  • “Available evidence indicates that CDAI, HBI, and 5 versions of PCDAI lack adequate measurement properties for use as a primary endpoint for phase 3 trials.”
  • “Endoscopic or radiology-based mucosal and histological examination may need to be considered as 1 outcome measurement.”

The second article describes a prospective cohort of 24 newly diagnosed children (<16 years).  The authors found the following:

  • At diagnosis, PCDAI had poor correlation with endoscopic disease activity (SES-CD)
  • After induction: 11/24 had inactive disease based on SES-CD; however, PCDAI had poor correlation.  Many children with active disease (SES-CD ≥3) had normalization of PCDAI as well as CRP.
  • Fecal calprotectin had better correlation.

Take-home point: These articles add to the growing literature regarding the lack of reliability of clinical activity indices.

Related blog posts:

Cumberland Island

Cumberland Island

 

 

Understanding the Reasons for Abnormal Liver Enzymes in Pediatric Inflammatory Bowel Disease

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A recent large single center study (Pusateri AJ et al. JPGN 2015; 60: 592-97) provides some very practical information regarding elevated liver enzymes in the setting of inflammatory bowel disease (IBD).  Because there are some serious liver diseases associated with IBD and due to the potential for liver toxicity from many of the medications, bumps in liver enzymes need to be carefully considered.

This retrospective study with 514 patients indicates that 77% of these elevations are transient. Table 1 lists the definitions (chronicity, severity) and patterns that were analyzed.  Transient elevations were broken down into brief (<30 days), prolonged <180 days, chronic >180 days and either intermittent or continuously abnormal. The three types were the following:

  • Hepatic: elevated ALT and/or AST; normal alkaline phosphatase (AP), GGT, and direct bilirubin (DB)
  • Cholestatic: elevated AP, GGT, and/or DB; normal ALT and AST
  • Mixed

Severity or degree was classified as follows:

  • 1 –peak liver enzyme 0-1 x ULN
  • 2 –peak liver enzyme >1-2 x ULN
  • 3 –peak liver enzyme >2-4 x ULN
  • 4 –peak liver enzyme >4 x ULN

Key findings:

  • 219 of 514 patients had 1 or more episode of abnormal liver enzymes; five patients with preexisting liver disease were excluded from the analysis.
  • Of 214 patients (152 with Crohn’s disease [CD], 62 with Ulcerative colitis [UC]) with abnormalities, 69% had a hepatitic pattern, 8% had a cholestatic pattern, and 23% had a mixed pattern. There was no association between the pattern and the final diagnosis (eg. idiopathic vs defined etiology)
  • Only 128 had adequate data to assess chronicity.  In this group, 77% had transient elevations (CD 75%, UC 80%)
  • 87% of elevations were considered idiopathic.  65% of patients with idiopathic elevation had levels < 2 times ULN.
  • Among patients with levels <2 times ULN, 95.3% had an idiopathic etiology.
  • Among patients with levels >4 times ULN, 63% had a benign idiopathic etiology
  • Figure 1 provides a pie chart of diagnoses.  Among the 12.6% with a specific etiology for elevated liver tests, drug toxicity was the most common reason: 51.9% were considered due to 6-MP therapy, 3.7% due to methotrexate, 3.7% due to acetaminophen.
  • Other identified causes among the 12.6% with a defined etiology included NAFLD in 11.1%, infections (CMV,EBV, Histoplasmosis) in 14.8%, cholelithiasis in 3.7%, autoimmune hepatitis in 3.7%, primary sclerosing cholangitis/overlap in 3.7%, and vascular malformation in 3.7%.

As with any retrospective study, there are a number of limitations, especially underdiagnosis given a lack of uniform approach to evaluation.  That being said, all patients had a minimum follow-up of at least nine months and most patients with prolonged liver enzyme elevation would have been examined closely.

Bottomline: This study provides reassurance that liver enzyme elevations are common in children with IBD, occurring in >40% of patients over 3 years at this center; most often these elevations are benign and transient.

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Venous Thromboembolism: A Good Question for Pediatric Collaboration

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Two recent clinical review articles (see below) indicate that most adults with inflammatory bowel disease (IBD) admitted to the hospital would benefit from venous thromboembolism (VTE) prophylaxis.  Since children with IBD have a lower risk of VTE, it is unclear whether more efforts at VTE prophylaxis are needed in the pediatric population.  Previous studies have shown that in those IBD patients less than 20 years, the incidence rate was 8.9 per 10,000 person years.  In contrast, in those IBD patients older than 60, the incidence rate was 54.6 per 10,000 person years (VTE with IBD | gutsandgrowth).

  • Inflammatory Bowel Dis 2015; 21: 1195-1203.
  • Inflammatory Bowel Dis 2015; 21: 1204-1213.

In the first article, the authors review common risk factors and disease-specific risk factors.  They state the following:

Because hospitalization puts the patient at greater risk for TE compared with an outpatient setting, all hospitalized patients should receive anticoagulant therapy in the absence of severe bleeding, even if the patients are in remission.

The second review describes epidemiological data, pathophysiology, and VTE prevention. They also state the following:

Currently, the most effective strategy for preventing VTE in hospitalized patients with IBD with active disease is prophylactic anticoagulation.  In fact, all of the current guidelines for the management of patients with IBD suggest the use of anticoagulants to prevent VTE.

The authors note that the rates of thromboprophylaxis are “still unacceptably low.”

Bottomline: In adults with active IBD, VTE prophylaxis is recommended. In the pediatric population due to the lower incidence of VTE, more study is needed –perhaps another project for ImproveCareNow.

Briefly noted:

Cochrane Review of Vedolizumab for Ulcerative Colitis.  Inflammatory Bowel Dis 2015; 21: 1151-59.  Based on four studies (n=606 patients) with low risk of bias, pooled analysis showed that vedolizumab was superior to placebo for induction of remission (RR=0.86), clinical response (RR=0.82), endoscopic remission (RR=0.82) and for achieving remission at 52 weeks in week 6 responders (RR=2.73).  No statistically significant difference was observed in the incidence of adverse events between vedolizumab and placebo.

Zoo Atlanta

Zoo Atlanta

Working on Transition Readiness

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A recent study (Gray WN, et al. Inflamm Bowel Dis 2015; 21: 1125-31) examines preparedness of patients with inflammatory bowel disease (IBD) on the verge of transitioning to adult gastroenterologists from pediatric gastroenterologists.

Using a population of 195 patients (16-25 years), the authors used the Transition Readiness Assessment Questionnaire (TRAQ).  Scoring system:

  • 5= Yes, I always do this when I need to
  • 4= Yes, I have started doing this
  • 3= No, but I am learning to do this
  • 2= No, but I want to learn
  • 1= No, I do not know how

Specific Readiness Skills & Mean Scores (more complete data listed in Table 3):

  • Taking medicines correctly and on own 4.66
  • Arranging for ride to medical appointment 4.39
  • Managing money and budgeting 3.69
  • Calling doctor about unusual change in health 3.64
  • Reordering and getting refills on time 3.60
  • Calling doctor’s office to schedule an appointment 3.09
  • Getting financial help with school or work 2.92
  • Knowing what health insurance covers 2.60
  • Applying for health insurance if coverage lost 2.44

Key finding: “Only 5.6% older adolescents/young adults …met our institutional benchmark.”

To help with transition readiness the authors recommend the CDHNF/NASPGHAN Transition Checklist for parents and starting on transition issues between 12-15 years of age.  Transition checklist available here: Transitioning a Patient With IBD From Pediatric to Adult Care –this is a simple 2-page handout!

Conclusion: Most patients need more work on transition readiness.  If patients are not prepared, it is more likely that this will lead to medical setbacks.

Briefly noted:

“Exercise Decreases Risk of Future Active Disease in Patients with Inflammatory Bowel Disease in Remission” Inflammatory Bowel Dis 2015; 21: 1063-71. This prospective study used the CCFA’s Partners’ internet-based cohort. 227 of 1308 (17.4%) Crohn’s disease (CD) patients and 135 of 549 (24.6%) Ulcerative colitis/indeterminate colitis (UC/IC) patients developed active disease after 6 months.  Key finding: Higher exercise level was associated with decreased risk of active disease for CD (adjusted relative risk 0.72) and UC/IC (adjusted relative risk 0.78).  Take-home point: While there are several limitations to this study, it does seem likely that regular physical exercise is a good idea (not just in patients with IBD).  In this population, subjective markers of disease activity (sCDAI and SCCAI) improved in those who exercised more.

Zoo Atlanta

Zoo Atlanta