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.

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.

From ImproveCareNow: Resources for Mind Body Interventions

From ImproveCareNow: Resources for Mind Body Interventions

The above linked-website has links to many others for patients and providers: meditation, mindfulness, yoga and guided imagery.  The links on this page borrowed from Chelly Dykes and KT Park who credits Dr. Sindu Vellanki and Dr Ann Ming Yeh from Stanford.

 

Literature on these topics (also from ImproveCareNow): Mind Body Interventions and IBD

Mind Body Interventions and IBD – Journal Articles

Overview:

  • Yeh, A. M., Wren, A., & Golianu, B. (2017). Mind–Body Interventions for Pediatric Inflammatory Bowel Disease. Children, 4(4), 22. doi:10.3390/children4040022
  • Mindfulness/ Meditation/ Mindfulness based Stress Reduction (MBSR):
  • Kabat-Zinn, J., Lipworth, L., Burney, R., & Sellers, W. (1987). Four-Year Follow-Up of a Meditation-Based Program for the Self-Regulation of Chronic Pain: Treatment Outcomes and Compliance. The Clinical Journal of Pain, 3(1), 60.

**Note: This is an overview of MBSR, not IBD specific

Mindfulness:

  • Neilson, K., Ftanou, M., Monshat, K., Salzberg, M., Bell, S., Kamm, M. A., . . . Castle, D. (2016). A Controlled Study of a Group Mindfulness Intervention for Individuals Living With Inflammatory Bowel Disease. Inflammatory Bowel Diseases, 22(3), 694-701.
  • Jedel, S., Hoffman, A., Merriman, P., Swanson, B., Voigt, R., Rajan, K., . . . Keshavarzian, A. (2014). A Randomized Controlled Trial of Mindfulness-Based Stress Reduction to Prevent Flare-Up in Patients with Inactive Ulcerative Colitis. Digestion, 89(2), 142-155.
  • Hood, M. M., & Jedel, S. (2017). Mindfulness-Based Interventions in Inflammatory Bowel Disease. Gastroenterology Clinics of North America, 46(4), 859-874.
  • Berrill, J. W., Sadlier, M., Hood, K., & Green, J. T. (2014). Mindfulness-based therapy for inflammatory bowel disease patients with functional abdominal symptoms or high perceived stress levels. Journal of Crohns and Colitis,8(9), 945-955. doi:10.1016/j.crohns.2014.01.018
  • Gerbarg, P. L., Jacob, V. E., Stevens, L., Bosworth, B. P., Chabouni, F., Defilippis, E. M., . . . Scherl, E. J. (2015). The Effect of Breathing, Movement, and Meditation on Psychological and Physical Symptoms and Inflammatory Biomarkers in Inflammatory Bowel Disease.Inflammatory Bowel Diseases,21(12), 2886-2896.

Clinical Hypnosis:

  • Keefer, L., Taft, T. H., Kiebles, J. L., Martinovich, Z., Barrett, T. A., & Palsson, O. S. (2013). Gut-directed hypnotherapy significantly augments clinical remission in quiescent ulcerative colitis. Alimentary Pharmacology & Therapeutics,38(7), 761-771.
  • Mawdsley, J. E., Jenkins, D. G., Macey, M. G., Langmead, L., & Rampton, D. S. (2008). The Effect of Hypnosis on Systemic and Rectal Mucosal Measures of Inflammation in Ulcerative Colitis. The American Journal of Gastroenterology,103(6), 1460-1469.
  • Shaoul, R., Sukhotnik, I., & Mogilner, J. (2009). Hypnosis as an Adjuvant Treatment for Children With Inflammatory Bowel Disease. Journal of Developmental & Behavioral Pediatrics,30(3), 268.
  • Vlieger, A., Govers, A., Frankenhuis, C., & Benninga, M. (2010). Hypnotherapy for children with functional abdominal pain or irritable bowel syndrome: Long term follow-up. European Journal of Integrative Medicine,2(4), 191.

Yoga: 

IBS + Yoga:

  • Schumann, D., Anheyer, D., Lauche, R., Dobos, G. Langhorst, J., Cramer, H. Effect of Yoga in the Therapy of Irritable Bowel Syndrome: A Systematic Review. Clin. Gastroenterol. Hepatol.  2016, 14, 1720-1731.
  • Selvan, S. R., Kavuri, V., Selvan, P., Malamud, A., & Raghuram, N. (2015). Randomized clinical trial study of Yoga therapy for Irritable Bowel Syndrome (IBS). European Journal of Integrative Medicine,7, 23.
  • Kuttner, L., Chambers, C., Hardial, J., Israel, D., Jacobson, K., Evans, K. A Randomized Trial of Yoga for Adolescents with Irritable Bowel Syndrome. Pain Research & Management 2006, 11, 217-223.
  • Evans, S., Lung, K., Seidman, L., Sternlieb, B., Zeltzer, L., & Tsao, J. (2014). (567) Iyengar yoga for adolescents and young adults with irritable bowel syndrome (IBS). J. Pediatri. Gastroenterol. Nutri. 2014, 59, 244-253.

IBD + Yoga:

 

Here’s What I Really Want to Know about an MRE Study –What is the Correlation with PGA?

A nice pediatric study (CG Sauer et al. JPGN 2016; 62: 378-83) provides data on 101 children from a single center who underwent MRE to evaluate their Crohn’s disease.  This study was a retrospective chart review using a prospectively maintained MRE database.  All of the children in this study underwent MRE greater than 180 days after diagnosis.  MRE was ordered at the discretion of the treating gastroenterologist. Median followup was 2.8 years after MRE.

Key findings:

  • MRE correlated with meaningful clinical outcomes. Of the 65 with active inflammation on MRE, only 44.6% achieved clinical remission (another 30% progressed to mild disease activity). Of the 36 without active inflammation, 88.9% achieved clinical remission.
  • Children with active inflammation on MRE were more likely to undergo surgery (18.5% vs. 2.8%) and more likely to have medication changes (44.6% vs. 8.3%).

While this population may have had more disease than those who did not undergo MRE (since it was done at the discretion of gastroenterologist), what would interest me would be the correlation with the physician global assessment.  A rough calculation would suggest that only 40% of these patients achieved a clinical remission which is well below ImproveCareNow reported benchmarks, but not much different from previous studies using objective markers.  Furthermore, it would be of interest to look at whether individual clinicians incorporated their abnormal MREs into their assessment of PGA.  If the patient was doing well clinically but their MRE was markedly abnormal or even mildly abnormal, were these patients classified as in remission or otherwise.

My take: MRE is an excellent & expensive tool to assess for mucosal healing.  As our treatments continue to improve, MRE will be useful to monitor our progress.  How we incorporate our objective markers with our clinical markers needs further work.

Related blog posts:

 

Why ImproveCareNow is Needed

A few recent articles make a strong argument for collaborative networks, like ImproveCareNow, to improve data collection to determine the most effective therapies.

  1. Kierkus J, et al. JPGN 2015; 60: 580-85.
  2. Audu GK, et al. JPGN 2015; 60: 586-91
  3. Dotson JL, et al. Inflamm Bowel Dis 2015; 21: 1109-14
  4. Saps M, et al. JPGN 2015; 60: 645-53.

A brief description of each study.

1. This study presented a multi-center randomized open-label trial of 99 pediatric patients with Crohn’s disease (CD) who were administered infliximab (IFX) along with an immunomodulator (azathioprine or methotrexate).  After a 10 week induction, 84 were randomized to either monotherapy for 54 weeks or dual therapy for 26 weeks. The authors did not find significant differences in response between the groups.  However, they reached a conclusion: “Twenty-six weeks likely represent (sic) the safe duration of combined IFX/immunomodulator therapy in our sample of pediatric patients with CD.”

2. The second study described three cases of chronic recurrent multifocal ostesomyelitis (CRMO) associated with inflammatory bowel disease.  They tried to identify all pediatric cases in UK in the last 10 years. (As an aside, I have treated one teenager with CRMO and ulcerative colitis.)

3. The third study is a retrospective single center of 30 patients with pediatric Crohn’s disease (CD) who developed intra-abdominal abscesses (IAA) over a 12-year period.  The authors note that this is “the largest single-center review of children and adolescents with CD and IAA to date.” Yet due to the small sample size, the study provides little guidance on this important medical problem; there were no predictors of successful medical or percutaneous drainage therapy.  In addition, with the increasing use of biologics, the authors note that “the issue of which patients will eventually require surgery is even less clear.” Changes in imaging (eg. MRE) and changes in medical management (eg. more enteral nutrition and less corticosteroids) are not discussed.

4. The fourth study is a comprehensive review of randomized placebo-controlled pharmacological clinical trials in children with functional abdominal pain disorders.  They found “no evidence to support the use of most commonly used drugs in children. Only 7 pharmacological RCTs on AP-FGIDs in children were found. Most studies were single center based and had a small sample size.  The methods and outcomes were heterogeneous…We found a considerable risk of bias in most studies…There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures.”

Each of these studies makes a compelling argument for collaborative research networks.  The first study had a relatively small number of patients, short follow-up period, lack of blinding, and numerous methodological limitations.  How did the authors determine that 26 weeks was the time to stop dual therapy? Among adults with CD, a well-designed SONIC study (NEJM 2010; 362: 1383) showed the superiority of dual therapy during the study period.  In children, because of concerns about thiopurine safety, the best approach is still unclear. The second study identified only three patients despite examining a large population.  Similarly, the third study describes 30 patients with a common complication of CD but provides little insight.

The fourth study is a cautionary tale illustrating the lack of progress due to the absence of collaborative research.  Reports indicate a high prevalence of functional abdominal pain; one study indicated that abdominal pain affects “38% of school children weekly” (J Pediatr 2009; 154: 322-6).  In fact, studies on the high prevalence of this disorder dates back for 60 years (Apley, 1975; Apley & Hale, 1973; Apley & Naish, 1958). Despite the prevalence of this problem, the data for all of the treatments is poor.  The lack of progress in defining treatments for functional abdominal pain is multifactorial, including the following:

  • Cost: For many of the available treatments, there is not a financial incentive to conduct research.
  • Biomarker: lack of objective markers for improvement
  • Disease Stigma: many people attribute functional disorders as being due solely to psychological factors
  • Physician Champions: in pediatric gastroenterology, it took concerted physician efforts over many years to develop ImproveCareNow.  Similar physician champions would be needed to improve the outcomes for children with functional disorders

Bottomline: While ImproveCareNow has a lot of work ahead including improving data reliability and ascertaining accurate outcome measures, I think the effort is forward-thinking and will make a difference in understanding and treating children with IBD.  ImproveCareNow has more than 600 participating pediatric gastroenterologists and more than 20,000 patients. What I would like to see is a sister network to address the morbidity from functional disorders so that in 60 years (or sooner), we will be better equipped to treat children with abdominal pain that is not due to IBD.

Related blog posts:

Fox Theater

Fox Theater

An Oral Oligonucleotide in the Crohn’s Treatment Pipeline & Smart Patients

The preliminary data are in from a phase II study regarding Mongerson, a oral pill for Crohn’s disease.

Here’s the link: Oral oligonucledotide shows efficacy, safety in Crohn’s

Here’s an excerpt from GI & Hepatology News:

Fourteen days of daily treatment with mongersen, an oral, antisense oligonucleotide, safely produced remissions in two-thirds of patients with Crohn’s disease in a phase II study with a total of 163 patients…

Mongensen “is not an anti-inflammatory drug. It removes a brake on the normal immunosupressant mechanism in the gut, and that is why the effect is long lasting. It allows TGF [transforming growth factor]-beta to work again [as an endogenous immunosuppressant] and promote healing,” said Dr. Monteleone, a professor of gastroenterology at the University of Rome Tor Vergata.

Oligonucleotide blockade of the production of the Smad7 intracellular protein prevented the inhibitory effect of Smad7 on TGF-beta and thus allowed TGF-beta to inhibit cytokine production and T lymphocyte signaling (J. Clin. Invest. 2001;108:601-9).

From ImproveCareNow — Smart Patients Online Community -may be helpful resource for families:

There are many social networks and online communities for IBD, but we have chosen to partner with the Smart Patients team because their custom-built, disease-specific forums offer a truly safe, warm and engaging experience for users. Smart Patients also offers conversation tagging, and clearly defined community norms, which means community members are highly likely to find the answers they need and highly unlikely to be trolled. And because the conversations are arranged using tags and completely searchable, you can always find what you’re looking for.

The Smart Patients team and ImproveCareNow have partnered to create an online IBD community that is supportive and also powerful. The Smart Patients IBDcommunity has the power to improve health and health care systems through patient and family peer-to-peer learning.

 

ImproveCareNow Video

A recent (short ~2:30) ImproveCareNow (ICN) Video explains how ImproveCareNow is a forward-thinking network and how it has the potential to lead to better outcomes for children with inflammatory bowel disease.

If you are part of ICN, this video may help explain to your patients what ICN is all about.

In PURSUIT of Better Treatment for Ulcerative Colitis

Patient education materials:

#1  Ulcerative Colitis For Dummies | UC Patient Resource This link connects to a free educational book promoted by Salix pharmaceuticals.  In order to receive a free download, you have to register and include your email.  I have not read this book but other similar books (eg. Colonoscopy for Dummies) by Salix have been well-written.

#2 This link, ow.ly/sPX95, is to the ImproveCareNow visit planner website.  It poses of ~ 8 questions and a text box  for “my list of things I’m concerned about and questions that I have.”  Families that use this planner may help themselves achieve more comprehensive care.

Anyone who follows this blog knows that I really enjoy a good study acronym.  The Program of Ulcerative Colitis Research Studies Utilizing an Investigational Treatment (PURSUIT) is responsible for two papers in the most recent Gastroenterology issue:

  • Gastroenterol 2014; 146: 85-95
  • Gastroenterol 2014; 146: 96-109

PURSUIT is composed of >200 sites from around the world.  The first study was a combined phase 2 and phase 3 study. It enrolled 1064 adults with moderate to severe ulcerative colitis (UC) who were randomly assigned to either placebo, 200/100 mg or 400/200 mg of SC golimumab at 0 and 2 weeks.  All patients were naive to previous anti-TNF therapies. The average duration of disease was 6 years among the participants. The primary endpoint of the phase 3 part of this study was the clinical response at 6 weeks.  Clinical response was at least a 30% improvement and a ≥3-point improvement in the Mayo score. At baseline, the average Mayo score was 8.

  • The golimumab groups had response rates of 51.8% and 55.0% respectively compared to 29.7% for placebo.
  • Approximately 18% of patients achieved a clinical remission with treatment compared with 6% of placebo patients.
  • Approximately 10% had healed mucosa compared with ~4% in the placebo group.
  • Adverse events: Rates of serious infection were 1.8% for the active treatment group compared with 0.5% for placebo-treated patients.  In the 400/200 mg dosing group, there was 1 death attributed to peritonitis and sepsis after multiple procedures for ischiorectal abscess repair.  In addition, a single case of demyelination was noted in this group.

The second study, a phase 3 double-blind trial, evaluated the efficacy of maintenance treatment of 50 mg or 100 mg SC every 4 weeks in those with a successful induction (n=464).  This study took place at 251 centers between 2007-2011. At 54 weeks, the actively-treated gourds had maintained a clinical response, using the Mayo score, in 47.1% and 50.6% respectively compared to 31.4% for placebo.  Antibodies to golimumab developed in 2.9%, two-thirds of these antibodies were neutralizing.  Antibody formation was lower in those receiving concomitant immunomodulators. 4 cases of tuberculosis were noted from endemic regions despite previous screening.  Overall, infections occurred in 28% of those treated with placebo compared with 39% of those treated with golimumab.

During the course of the study, three deaths were reported, all in the 100 mg golimumab maintenance group.  The causes were malnutrition/sepsis, cardiac failure/thrombosis, and disseminated tuberculosis (patient was receiving isoniazid). After the study, another 6 deaths were reported, including two in the placebo group.  Three malignancies were reported through week 54 in patients receiving golimumab maintenance, two of these presented in the induction period while receiving placebo rectal cancer and thyroid cancer) and one (lung adenocarcinoma) occurred in a patient with a 40-year smoking history who received golimumab for induction and maintenance.

Taken together, about 25% of patients randomized to and maintained on golimumab achieved a clinical response lasting >1 year; similarly, about 17% had clinical remission at 1 year.

In the commentary (page 13-15), Stephen Hanauer notes that better response was noted with higher serum levels and there remains “a strong possibility that optimal dosing was not achieved.”  He and the authors comment on the observation that less-severe patients had a better response, indicating that  “greater disease severity may be correlated with more rapid clearance.”

Bottomline: These studies demonstrate that golimumab is an effective treatment for UC with a similar risk of adverse reactions as other anti-TNF agents.  The published studies are complicated and take some time to analyze.

Plus more references:

Gastroenterol 2014; 146: 110-18. “Adalimumab therapy is associated with reduced risk of hospitalization in patients with ulcerative colitis.” Data for this studies was derived from ULTRA1 and ULTRA2 trials with 963 patients.  Risk for hospitalization, whether due to UC or all-causes, was reduced between 40-50% compared to placebo within the first 8 weeks of adalimumab administration.

Clin Gastroenterol Hepatol 2013; 11: 1538-49.  Excellent review on pouchitis. Figure 5 (pg 1545) provides a nice treatment algorithm.  Initial approach is antibiotics (metronidazole or ciprofloxacin); in those responsive, either prn therapy or chronic treatment.  In those not responsive, look for pathogens (eg. CMV and C difficile) or determine it is immune-mediated (PSC-associated, IgG4-associated, or autoimmune).  The immune-mediated may respond to 5-ASA/budesonide or immunomodulators.

Clin Gastroenterol Hepatol 2013; 11: 1601-08. This case-control study with 141 UC controls and 59 patients who developed colorectal neoplasia found that increased inflammation was associated with colorectal neoplasia.  Use of immune modulators reduced the risk of colorectal neoplasia.

Related blog post:

Simponi (Golimumab) Approved for Ulcerative Colitis | gutsandgrowth